TW202330545A - Novel compounds - Google Patents

Abstract

The invention relates to novel compounds having the general formula Ic wherein R1, R2, R3, R8, R9, R<SP>X</SP>, A1, A2, W and n are as described herein, composition including the compounds and methods of using the compounds.

Description

novel compound

The present invention relates to organic compounds useful in the treatment and/or prophylaxis of mammals, and in particular to compounds that modulate NLRP3 inhibition.

The present invention provides novel compounds of formula Ic, Ic wherein A ¹ is -N- or -CR ¹⁰ -; A ² is -O-, -NH-, -NCH ₃ - or -S-; R ¹ is H, halo, alkyl, haloalkyl, halo Alkoxy, cyano, alkoxy, cycloalkyl or alkylsulfonyl; R ⁹ is H, alkyl, halo or cyano; or R ¹ and R ⁹ form a 4-membered to 6-membered cycloalkyl group or a heterocycle containing a single O heteroatom; R ^is H, halo, alkyl, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxyalkyl, or ^hydroxyalkyl and R is H, halo or alkyl, wherein at least one of ^R2 and ^R3 is not H; ^R8 is H or halo; ^R10 is selected from H, alkyl, acetyl, alkylamino, Dialkylamino, hydroxyalkyl, hydroxyalkylalkyl, cyano, halo, haloalkyl, alkoxy, haloalkoxy and NR'R'', where R' and R'' are independently Selected from H and alkyl, or R' and R'' form a 4-membered to 6-membered N-containing heterocyclic ring or a 5-membered lactamide ring optionally substituted by -OH with the N atoms attached to them; n can be is 0 or 1; R ^X is H, alkyl, alkoxyalkyl or hydroxyalkyl; W is selected from 4 to 10 membered heterocycles containing up to 3 heteroatoms independently selected from N and O, Among them, the maximum number of O heteroatoms is 1, depending on the situation, 1 or 2 are selected from pendant oxy, -OH, halo, alkyl, alkoxyalkyl, alkylamino, dialkylaminoalkane hydroxyalkyl, cyano, haloalkyl, alkylester, alkylsulfon, cycloalkyl, heterocycle containing a single O heteroatom, cycloalkyl substituted with -OH, substituted with -OH Substituents of cycloalkyl-CH ₂ -, 6-membered heteroaryl substituted by alkoxy and 5-membered heteroaryl having 2 N heteroatoms, containing up to 2 independently selected from N and O 4- to 6-membered heterocyclic ring -CH ₂ -, wherein the maximum number of O heteroatoms is 1, optionally substituted by alkyl, optionally 1 to 2 independently selected from -OH, alkylamine 3- to 6-membered cycloalkyl substituted with substituents of -OH and dialkylamino; 4-membered cycloalkyl-CH optionally substituted with 1 or 2 substituents independently selected from -OH and alkyl ₂ -, and a 5-membered heteroaryl-CH ₂ - containing 2 N heteroatoms; and pharmaceutically acceptable salts.

Furthermore, the present invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers.

The NOD-like receptor (NLR) family, pyrin domain–containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process and abnormal activity of which is a genetic disorder (eg, Cryopyrin-associated periodic syndrome ( CAPS)) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis.

NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental and host-derived factors. Upon activation, NLRP3 binds to the apoptosis-associated speck-like protein (ASC) that contains the caspase activation and recruitment domain. ASC subsequently aggregates to form large aggregates called ASC specks. The polymerized ASC in turn interacts with the cysteine protease caspase-1 to form a complex called the inflammasome. This leads to the activation of caspase-1, which cleaves the precursor forms of the pro-inflammatory cytokines IL-1β and IL-18 (known as pro-IL-1β and pro-IL-18, respectively), thereby activating these cells hormone. Caspase-1 also mediates a form of inflammatory cell death known as pyroptosis. ASC puncta also recruit and activate caspase-8, which processes pro-IL-1β and pro-IL-18 and triggers apoptotic cell death.

Caspase-1 cleaves pro-IL-1β and pro-IL-18 into their active forms, which are secreted from cells. Active caspase-1 also cleaves gasdermin-D to trigger pyroptosis. Caspase-1, through its control of the pyroptotic cell death pathway, also regulates the release of alarmin molecules such as IL-33 and high mobility group box 1 (HMGB1). Caspase-1 also cleaves intracellular IL-1R2, causing its degradation and allowing the release of IL-1α. In human cells, caspase-1 also controls the processing and secretion of IL-37. A variety of other caspase-1 substrates, such as the cytoskeleton and components of the glycolytic pathway, contribute to caspase-1-dependent inflammation.

NLRP3-dependent release of ASC specks into the extracellular milieu, where it activates caspase-1, induces processing of caspase-1 substrates and propagates inflammation.

Cytokines derived from the activity of NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to shape the immune response to infection and injury. For example, IL-1β signaling induces the secretion of the pro-inflammatory cytokines IL-6 and TNF. IL-1β and IL-18 act synergistically with IL-23 to induce IL-17 production by memory CD4 Th17 cells and by γδ T cells in the absence of T cell receptor binding. IL-18 and IL-12 also act synergistically to induce IFN-γ production by memory T cells and NK cells that drive Th1 responses.

The inherited CAPS disorders Muckle-Wells syndrome (MWS), familial cold-induced autoinflammatory syndrome (FCAS), and neonatal multiple systemic inflammatory syndrome (NOMID) are caused by gain-of-function mutations in NLRP3 and are This defines NLRP3 as a key component of the inflammatory process. NLRP3 is also involved in the pathogenesis of a variety of complex diseases, notably including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout.

NLRP3 appears to play a role in diseases of the central nervous system, and lung diseases have also been shown to be affected by NLRP3. NLRP3 has also been implicated in a number of central nervous system conditions including Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease disease), cerebral malaria, and pneumococcal meningitis (Walsh et al., Nature Reviews, 15: 84-97, 2014; and Dempsey et al. Brain. Behav. Immun. 201761: 306-316). NLRP3 has also been shown to play a role in many lung diseases including chronic obstructive pulmonary disease (COPD), asthma (including steroid-resistant asthma), asbestosis, and silicosis (De Nardo et al., Am. J. Pathol., 184: 42-54, 2014; and Kim et al. Am J Respir Crit Care Med. 2017 196(3): 283-97). In addition, NLRP3 plays a role in the development of liver disease, kidney disease and aging. Many of these associations were defined using Nlrp3 ^{− / −} mice, but specific activation of NLRP3 in these diseases is also known. In type 2 diabetes (T2D), deposition of amylin polypeptide in the pancreas activates NLRP3 and IL-1β signaling, leading to cell death and inflammation.

Several small molecules have been shown to inhibit the NLRP3 inflammasome. Glibenclamide inhibits IL-1β production at micromolar concentrations in response to activation of NLRP3 but not NLRC4 or NLRP1. Other previously characterized weak NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy-β-nitrostyrene, and dimethylsulfoxide (DMSO), but these agents have limited potency and are nonspecific of.

Current treatments for NLRP3-associated diseases include biologics that target IL-1. These biologics are the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1β antibody canakinumab, and the soluble decoy IL-1 receptor rilonacept. These approaches have proven successful in the treatment of CAPS, and these biologics have been used in clinical trials for other IL-1β-related diseases.

There is a need to provide compounds with improved pharmacological and/or physiological and or physicochemical properties and/or compounds which provide useful alternatives to known compounds.

The present invention provides novel compounds of formula Ic, Ic wherein A ¹ is -N- or -CR ¹⁰ -; A ² is -O-, -NH-, -NCH ₃ - or -S-; R ¹ is H, halo, alkyl, haloalkyl, halo Alkoxy, cyano, alkoxy, cycloalkyl or alkylsulfonyl; R ⁹ is H, alkyl, halo or cyano; or R ¹ and R ⁹ form a 4-membered to 6-membered cycloalkyl group or a heterocycle containing a single O heteroatom; R ^is H, halo, alkyl, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxyalkyl, or ^hydroxyalkyl and R is H, halo or alkyl, wherein at least one of ^R2 and ^R3 is not H; ^R8 is H or halo; ^R10 is selected from H, alkyl, acetyl, alkylamino, Dialkylamino, hydroxyalkyl, hydroxyalkylalkyl, cyano, halo, haloalkyl, alkoxy, haloalkoxy and NR'R'', where R' and R'' are independently Selected from H and alkyl, or R' and R'' form a 4-membered to 6-membered N-containing heterocyclic ring or a 5-membered lactamide ring optionally substituted by -OH with the N atoms attached to them; n can be is 0 or 1; R ^X is H, alkyl, alkoxyalkyl or hydroxyalkyl; W is selected from 4 to 10 membered heterocycles containing up to 3 heteroatoms independently selected from N and O, Among them, the maximum number of O heteroatoms is 1, depending on the situation, 1 or 2 are selected from pendant oxy, -OH, halo, alkyl, alkoxyalkyl, alkylamino, dialkylaminoalkane hydroxyalkyl, cyano, haloalkyl, alkylester, alkylsulfon, cycloalkyl, heterocycle containing a single O heteroatom, cycloalkyl substituted with -OH, substituted with -OH Substituents of cycloalkyl-CH ₂ -, 6-membered heteroaryl substituted by alkoxy and 5-membered heteroaryl having 2 N heteroatoms, containing up to 2 independently selected from N and O 4- to 6-membered heterocyclic ring -CH ₂ -, wherein the maximum number of O heteroatoms is 1, optionally substituted by alkyl, optionally 1 to 2 independently selected from -OH, alkylamine 3- to 6-membered cycloalkyl substituted with substituents of -OH and dialkylamino; 4-membered cycloalkyl-CH optionally substituted with 1 or 2 substituents independently selected from -OH and alkyl ₂ -, and a 5-membered heteroaryl-CH ₂ - containing 2 N heteroatoms; and pharmaceutically acceptable salts.

The term "acetyl" means a -C(=0) _CH3 group.

The term "alkyl" denotes a monovalent straight or branched chain saturated hydrocarbon group of 1 to 6 carbon atoms. In some embodiments, unless stated otherwise, alkyl comprises 1 to 6 carbon atoms (C _1-6 -alkyl) or 1 to 4 carbon atoms (C _1-4 -alkyl). Examples of C _1-6 -alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl and pentyl. Particular alkyl groups are methyl and ethyl.

The term "alkoxy" denotes a radical of formula -OR', wherein R' is a C _1-6 -alkyl radical. Examples of C _1-6 -alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particular alkoxy groups include methoxy and ethoxy.

The term "alkoxyalkyl" refers to an alkyl group in which one of the hydrogen atoms of the alkyl group has been replaced with an alkoxy group. Specific examples of alkoxyalkyl are methoxymethyl and methoxyethyl.

The term "amino" means a _-NH2 group.

The term "alkylamino" refers to an amine group in which one of the hydrogen atoms of the amine group has been replaced by an alkyl group. A specific example is methylamine.

The term "alkylaminoalkyl" denotes an aminoalkyl group in which one of the hydrogen atoms of the amino group has been replaced by an alkyl group. Examples of alkylaminoalkyl groups include methylaminomethyl and methylaminoethyl.

The term "dialkylamino" refers to an amine group in which two of the hydrogen atoms of the amine group have been substituted with two alkyl groups. A specific example is a dimethylamine group.

The term "dialkylaminoalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been substituted with a dialkylamino group. Examples of dialkylaminoalkyl include (dimethylamino)methyl and (dimethylamino)ethyl. A specific example is (dimethylamino)methyl.

The term "aminoalkyl" refers to an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced with an amino group. Examples of aminoalkyl groups include aminomethyl and aminoethyl.

The term "ester" denotes a carboxyl group bridging two moieties attached to carbon atoms. Examples include methoxycarbonyl.

The term "alkyl ester" refers to an ester group in which one of the hydrogen atoms of the ester group has been replaced by an alkyl group. Specific examples are 2-methoxy-2-oxo-ethyl and 3-methoxy-3-oxo-propyl.

The term "sulfonyl" denotes a -S(O) ₂ - group.

The term "alkylsulfonyl" means a group of formula -S(O)2-R', where R' is an alkyl group. Specific examples of alkylsulfonyl groups include groups of formula -S(O)2-R', where R' is methyl.

The term "cycloalkyl" denotes a monocyclic or polycyclic saturated or partially unsaturated non-aromatic hydrocarbon. In some embodiments, unless otherwise specified, the cycloalkyl group contains 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, cycloalkyl is a saturated monocyclic or polycyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentenyl, spiro[3.3]heptyl, and the like. Specific examples include cyclobutyl, cyclopentyl and cyclohexyl. Other specific examples include cyclopropyl and cyclohexyl.

The term "cyano" denotes a -C≡N group.

The terms "halogen", "halide" and "halo" are used interchangeably herein and mean fluorine, chlorine, bromine or iodine. Specific halogens are fluorine and chlorine.

The term "haloalkyl" denotes a C _1-6 -alkyl group wherein at least one of the hydrogen atoms of the C _1-6 -alkyl group is substituted by the same or different halogen atoms. Examples of haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl. Specific examples are difluoromethyl, difluoropropyl and trifluoromethyl.

The term "haloalkoxy" denotes a C _1-6 -alkoxy group wherein at least one of the hydrogen atoms of the C _1-6 -alkoxy group is substituted by the same or different halogen atoms. Examples of haloalkoxy are difluoromethoxy, trifluoromethoxy, difluoroethoxy and trifluoroethoxy. Particular examples are difluoromethoxy and trifluoromethoxy.

The term "heteroaryl" alone or in combination denotes a monovalent aromatic heterocyclic monocyclic or bicyclic ring system of 5 to 12 ring atoms comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S , while the remaining ring atoms are carbon. Examples of heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxdiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazine Base, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, triazinyl, azuryl, diazinyl, isoxazolyl, benzofuryl, isothiazolyl, benzothienyl, indole base, isoindolyl, isobenzofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzodiazolyl, benzene Thiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolyl, quinazolinyl, quinazolyl and benzothiophenyl. A specific example of a heteroaryl group is imidazole.

The term "heterocycle ring (heterocycle ring or heterocycle)" denotes a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 10 ring atoms or 4 to 9 reducing atoms comprising 1 selected from N, O and S , 2 or 3 ring heteroatoms, and the remaining ring atoms are carbon. Examples of monocyclic saturated heterocyclic rings are tetrahydroaziridyl, diazolinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, Piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl and piperazinyl. Examples of polycyclic saturated heterocycles are azaspiroheptyl, diazaspiroheptyl, azaspirooctyl, diazospirooctyl, diazaspirononyl, oxazaspiroctyl and Oxadiazaspirononyl. Specific examples of 4-membered heterocyclic rings are tetrahydroaziryl and oxetanyl. Specific examples of 5-membered heterocycles are pyrrolidinyl, tetrahydrofuranyl and pyrrolidinyl. Specific examples of 6-membered heterocycles are piperidinyl, morpholinyl, tetrahydropyranyl and piperazinyl. A specific example of a 7-membered heterocycle is nitrogen. Specific examples of 8-membered heterocycles are azabicyclo[2.2.2]oct-4-yl and hexahydrofuro[3,4-c]pyrrol-5-yl. Specific examples of 9-membered heterocyclic rings are swainsonyl, octahydropyrrolo[2,3-c]pyridin-1-yl, diazaspironon-7-yl and hexahydro-2H-pyrrolo[3 ,4-b][1,4]oxazin-4-yl. Specific examples of 10-membered heterocyclic rings are octahydro-1,7-oxazin-1-yl and hexahydro-2H-pyrido[4,3-b][1,4]oxazin-4-yl.

The term "hydroxyl" means an -OH group.

The term "hydroxyalkyl" refers to an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by a hydroxy group. Examples of hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylethyl, hydroxymethylpropyl and dihydroxypropyl. Specific examples are hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxymethylethyl.

The term "lactamide ring" means a cyclic amide. A specific example is 2-oxypyrrolidin-1-yl.

The term "side oxy" means the divalent oxygen atom =O.

The term "pyrrolidinylalkyl" refers to an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been substituted with a pyrrolidinyl group. An example of pyrrolidinylalkyl is pyrrolidinylmethyl.

The term "pharmaceutically acceptable salts" refers to those salts which retain the biological effect and properties of the free base or free acid and which are not biologically or otherwise unfavorable. The salts are formed with inorganic acids such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, in particular hydrochloric acid, and with organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, Maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine Acid formation. Furthermore, such salts can be prepared by the addition of inorganic or organic bases to the free acids. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, Diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins. Compounds of formula I may also exist in zwitterionic form. Particularly preferred pharmaceutically acceptable salts of the compounds of formula I are the salts with formic acid and the salts with hydrochloric acid, resulting in the hydrochloride, dihydrochloride or trihydrochloride.

The abbreviation uM stands for micromole and is equivalent to the symbol µM.

The abbreviation uL means microliter and is equivalent to the symbol µL.

The abbreviation ug means microgram and is equivalent to the symbol µg.

Compounds of formula Ic may contain several asymmetric centers and may be in the form of optically pure enantiomers, mixtures of enantiomers (e.g. racemates), optically pure diastereomers, diastereomers A mixture of diastereomeric racemates, a diastereomeric racemate, or a mixture of diastereomeric racemates.

According to the Cahn-Ingold-Prelog sequence rule, the asymmetric carbon atom can be in "R" or "S" configuration.

Furthermore, an embodiment of the present invention provides a compound of formula Ic as described herein and a pharmaceutically acceptable salt or ester thereof, specifically provides a compound of formula Ic as described herein and a pharmaceutically acceptable salt thereof, More particularly provided are compounds of formula Ic as described herein.

One embodiment of the invention provides a compound of formula Ic as described herein, wherein ^A2 is -O- or -NH-.

One embodiment of the invention provides a compound of formula Ic as described herein, wherein ^A2 is -O-.

One embodiment of the invention provides a compound of formula Ic as described herein, wherein ^R is H, halo, alkyl, haloalkyl, haloalkoxy, cyano, alkoxy, cycloalkyl or alkyl sulfonyl; R ⁹ is H, alkyl, halo, or cyano; or R ¹ and R ⁹ form a 5-membered heterocycle containing a single O heteroatom.

One embodiment of the present invention provides a compound of formula Ic as described herein, wherein R ¹ is halo, alkyl, haloalkyl or cyano; R ⁹ is H; or R ¹ and R ⁹ form a heteroatom containing a single O 5-membered heterocycle.

One embodiment of the invention provides a compound of formula Ic as described herein, wherein R ¹ is halo or cyano and R ⁹ is H.

One embodiment of the invention provides a compound of formula Ic as described herein, wherein R ² is alkyl or alkoxyalkyl and R ³ is H.

One embodiment of the invention provides a compound of formula Ic as described herein, wherein R ⁸ is H.

One embodiment of the present invention provides a compound of formula Ic as described herein, wherein R is selected from ^{the group} consisting of H, alkyl, acetyl, alkylamine, dialkylamino, hydroxyalkyl, hydroxyalkylalkane group, cyano group, alkoxy group and NR'R'', wherein R' and R'' form a 4- to 5-membered N-containing heterocyclic ring optionally substituted by -OH with the N atom to which they are attached, or a 5-membered N-containing heterocycle member lactamide ring.

One embodiment of the present invention provides a compound of formula Ic as described herein, wherein R ¹⁰ is selected from H, cyano and alkoxy.

One embodiment of the invention provides a compound of formula Ic as described herein, wherein R ¹⁰ is H.

One embodiment of the invention provides a compound of formula Ic as described herein, wherein ^Rx is H, alkoxyalkyl or hydroxyalkyl.

One embodiment of the invention provides a compound of formula Ic as described herein, wherein ^Rx is H.

One embodiment of the present invention provides a compound of formula Ic as described herein, wherein W is selected from 4 to 10 membered heterocycles containing up to 3 heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is The number is 1, depending on the situation, 1 or 2 are selected from side oxygen, -OH, halo, alkyl, alkoxyalkyl, alkylamino, dialkylaminoalkyl, hydroxyalkyl, Substituents for haloalkyl, 4-membered cycloalkyl, 4-membered heterocycle containing 1 O heteroatom, -OH-substituted 4-membered cycloalkyl, and -OH-substituted 4-membered cycloalkyl-CH ₂ - Substituted, 4 to 6 membered heterocyclic ring -CH ₂ - containing up to 2 heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1, optionally substituted with alkyl, optionally - 3- to 6-membered cycloalkyl substituted by OH, alkylamino or dialkylamino, optionally 4-membered cycloalkyl substituted by 1 or 2 substituents independently selected from -OH and alkyl -CH ₂ -, and 5-membered heteroaryl -CH ₂ - containing 2 N heteroatoms.

One embodiment of the present invention provides a compound of formula Ic as described herein, wherein W is selected from 6 to 9 membered heterocycles containing up to 3 heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is The number is 1, optionally substituted by 1 or 2 substituents selected from side oxy, -OH, halo, alkyl and hydroxyalkyl, 6-membered heterocycle -CH ₂ - containing a single N heteroatom, Alkyl substituted, and 5-membered cycloalkyl substituted with dialkylamino.

One embodiment of the present invention provides a compound of formula Ic as described herein, wherein W is a 6-membered heterocycle comprising a single N heteroatom optionally substituted with alkyl or pendant oxy, or both alkyl and -OH ;

One embodiment of the present invention provides a compound of formula Ic as described herein, wherein A ¹ is -N- or -CR ¹⁰ -; A ² is -O- or -NH-; R ¹ is H, halo, alkyl , haloalkyl, haloalkoxy, cyano, alkoxy, cycloalkyl or alkylsulfonyl; R ⁹ is H, alkyl, halo or cyano; or R ¹ and R ⁹ form a single 5-membered heterocycle with O heteroatoms; R ^is H, halo, alkyl, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxyalkyl or hydroxyalkyl and ^R is H , halo or alkyl, wherein at least one of ^R2 and ^R3 is not H; ^R8 is H or halo; ^R10 is selected from H, alkyl, acetylalkylamino, dioxane Amino, hydroxyalkyl, hydroxyalkylalkyl, cyano, alkoxy, and NR'R'', where R' and R'' form, with the N atom to which they are attached, an optionally -OH-substituted 4-membered to 5-membered N-containing heterocyclic ring, or 5-membered lactamide ring; n can be 0 or 1; R ^X is H, alkoxyalkyl or hydroxyalkyl; W is selected from the group consisting of up to 3 independently 4- to 10-membered heterocycles with heteroatoms selected from N and O, wherein the maximum number of O heteroatoms is 1, optionally with 1 or 2 members selected from pendant oxy, -OH, halo, alkyl, Alkoxyalkyl, alkylamino, dialkylaminoalkyl, hydroxyalkyl, haloalkyl, 4-membered cycloalkyl, 4-membered heterocycle containing a single O heteroatom, 4-membered -OH substituted 4-membered cycloalkyl and 4-membered cycloalkyl-CH ₂ -substituted by -OH, 4- to 6-membered heterocyclic ring -CH ₂ - containing at most 2 heteroatoms independently selected from N and O , where the maximum number of O heteroatoms is 1, optionally substituted with alkyl, optionally 3- to 6-membered cycloalkyl substituted with -OH, alkylamino or dialkylamino, optionally 1 Or 4-membered cycloalkyl-CH ₂ -substituted by two substituents independently selected from -OH and alkyl, and 5-membered heteroaryl-CH ₂ -containing 2 N heteroatoms; and pharmaceutically acceptable of salt.

One embodiment of the invention provides a compound of formula Ic as described herein, wherein A ¹ is -N- or -CR ¹⁰ -; A ² is -O-; R ¹ is halo, alkyl, haloalkyl or cyano R ⁹ is H; or R ¹ and R ⁹ form a 5-membered heterocyclic ring containing a single O heteroatom; R ² is alkyl or alkoxyalkyl and R ³ is H; R ⁸ is H; R ¹⁰ is selected from H, cyano and alkoxy; n can be 0 or 1; R ^X is H; W is selected from 6 to 9 membered heterocycles containing up to 3 heteroatoms independently selected from N and O, Wherein the maximum number of O heteroatoms is 1, optionally substituted by 1 or 2 substituents selected from pendant oxy, -OH, halo, alkyl and hydroxyalkyl, 6-membered heteroatoms containing a single N heteroatom Ring -CH ₂ -, a 5-membered cycloalkyl group substituted by an alkyl group, and a 5-membered cycloalkyl group substituted by a dialkylamino group; and pharmaceutically acceptable salts.

One embodiment of the present invention provides a compound of formula Ic as described herein, wherein A ¹ is -N- or -CR ¹⁰ -; A ² is -O-; R ¹ is halo or cyano; R ⁹ is H; ^R2 is alkyl or alkoxyalkyl and ^R3 is H; ^R8 is H; ^R10 is H; n can be 0 or 1; ^RX is H; W is a 6-membered heteroatom containing a single N heteroatom ring, optionally substituted with alkyl or pendant oxy, or both alkyl and -OH; and pharmaceutically acceptable salts.

One embodiment of the present invention provides a compound of formula Ib, wherein the compound of formula Ib is a compound of Ic Ib.

Compounds of formula Ib may contain several asymmetric centers and may be in the form of optically pure enantiomers, mixtures of enantiomers (e.g. racemates), optically pure diastereomers, diastereomers A mixture of diastereomeric racemates, a diastereomeric racemate, or a mixture of diastereomeric racemates.

Furthermore, the embodiments of the present invention provide compounds of formula Ib described herein and pharmaceutically acceptable salts or esters thereof, specifically provide compounds of formula Ib described herein and pharmaceutically acceptable salts thereof, more In particular there is provided a compound of formula Ib as described herein.

One embodiment of the present invention provides a compound according to formula Ib described herein, wherein A ¹ is -N- or -CR ¹⁰ -; A ² is -O-, -NH-, -NCH ₃ - or -S-; R ¹ is H, halogen, alkyl, haloalkyl, haloalkoxy, cyano, alkoxy or cycloalkyl; R ⁹ is H or halogen; or R ¹ and R ⁹ form a 4- to 6-membered cycloalkane or a heterocycloalkyl ring containing a single O heteroatom; R ^is H, halo, alkyl, cyano, haloalkoxy, haloalkyl, alkoxy, or alkoxyalkyl, and ^R is H, halogen or alkyl, wherein at least one of R ² and R ³ is not H; R ⁸ is H or halo; R ¹⁰ is selected from i. H, ii. alkyl, iii. hydroxyalkyl, iv cyano, v. halogen, v. haloalkyl, vi. alkoxy, vii. haloalkoxy, viii. 5- to 6-membered heterocycles containing 1 or 2 N atoms, optionally modified Halo or methyl substitution, or ix. NR'R'', wherein R' and R'' are independently selected from H or alkyl, or R' and R'' form 4 with the N atom to which they are attached N-membered to 6-membered heterocyclic ring or 5-membered lactamide ring; n can be 0 or 1; W is a heterocycloalkyl group substituted by 1 to 2 substituents independently selected from the following items as appropriate: Oxy, -OH, alkyl, alkylamino, alkylaminoalkyl, amino, aminoalkyl, cyano, cycloalkyl, or amino-substituted cycloalkyl, halogen, dioxane Amino, dialkylaminoalkyl, ester, haloalkyl, hydroxyalkyl, sulfonyl or pyrrolidinylalkyl, or W is optionally 1 to 2 independently selected from the following 3- to 6-membered cycloalkyl substituted by substituents: –OH, alkyl, alkylamino, amine, dialkylamino, halogen, haloalkyl and tertiary butyl N-methylcarbamate; and pharmaceutically acceptable salts.

One embodiment of the present invention provides a compound according to formula Ib described herein, wherein A ¹ is -N- or -CR ¹⁰ -; A ² is -O- or -NH; R ¹ is halogen, haloalkyl, cyano , alkoxy or cycloalkyl; R ⁹ is H or halogen; or R ¹ and R ⁹ form a 5-membered heterocycle containing a single O heteroatom; R ² is H, alkyl, cyano, haloalkyl, alkane Oxygen or alkoxyalkyl, and R ³ is H or alkyl, wherein at least one of R ² and R ³ is not H; R ⁸ is H; R ¹⁰ is selected from H or methyl; n can is 0 or 1; W is selected from the ring system: (A), (B), (C); (D), (E), or (F) Among them, B ¹ is -N- or -CH-; B ² is -CHR ⁴ - or -NCH ₃ ; B ³ is -CHR ⁵ -, -O- or -NR ⁶ - B ⁴ is -O- , -CH ₂ -, -NH-, -C(=O)-; B ⁵ is -CH-; B ⁶ is -NH-; B ⁷ is -CH ₂ -; B ⁸ is -N-; B ⁹ is -CH ₂ -; B ¹⁰ is -CHR ⁷ -; R ⁴ is H or dialkylaminoalkyl; R ⁵ is H, -OH, alkylamino or hydroxyalkyl; R ⁶ is H or alkyl ; R ⁷ is -OH; wherein W may only have up to 2 heteroatoms and 2 non-hydrogen substituents; wherein if W is ring system (C), ring system (E), or B ¹ is -N-, then n is 0; and pharmaceutically acceptable salts.

One embodiment of the present invention provides a compound according to formula Ib described herein, wherein A ¹ is -N- or -CR ¹⁰ -; A ² is -O- or -NH; R ¹ is halogen, haloalkyl, cyano or alkoxy; R ⁹ is H or halogen; or R ¹ and R ⁹ form a 5-membered heterocycle containing a single O heteroatom; R ² is H, alkyl, cyano, haloalkyl, or alkoxyalkyl , and R ³ is H or alkyl, wherein at least one of R ² and R ³ is not H; R ⁸ is H; R ¹⁰ is selected from H or methyl; n can be 0 or 1; W is selected Self-loop system: (A), (D), (E), or (F) Wherein, B ¹ is -CH-; B ² is -CHR ⁴ -; B ³ is -NR ⁶ - B ⁴ is -CH ₂ - or -C(=O)-; R ⁴ is H; R ⁶ is H or alkyl; wherein W may only have up to 2 heteroatoms and 2 non-hydrogen substituents; wherein if W is a ring system (E), then n is 0; and pharmaceutically acceptable salts.

One embodiment of the present invention provides a compound according to formula Ib described herein, wherein A ¹ is -N- or -CR ¹⁰ -; A ² is -O-; R ¹ is halogen, haloalkyl, cyano or alkoxy R ⁹ is H or halogen; R ² is alkyl, cyano or alkoxyalkyl, and R ³ is H; R ⁸ is H; R ¹⁰ is H; n can be 0 or 1; W is selected Self-loop system: (A), (D), (E), or (F) Wherein, B ¹ is -CH-; B ² is -CHR ⁴ -; B ³ is -NR ⁶ - B ⁴ is -CH ₂ - or -C(=O)-; R ⁴ is H; R ⁶ is H or alkyl; wherein W may only have up to 2 heteroatoms and 2 non-hydrogen substituents; wherein if W is a ring system (E), then n is 0; and pharmaceutically acceptable salts.

One embodiment of the present invention provides a compound according to formula Ib described herein, wherein A ¹ is -N- or -CR ¹⁰ -; A ² is -O-; R ¹ is halogen, haloalkyl or cyano; R ⁹ is H; R ² is alkyl and R ³ is H; R ⁸ is H; R ¹⁰ is H; n can be 0 or 1; W is selected from ring systems: (A), (D), or (E), wherein, B ¹ is -CH-; B ² is -CHR ⁴ -; B ³ is -NR ⁶ - B ⁴ is -CH ₂ -; R ⁴ is H; R ⁶ is alkyl; having only up to 2 heteroatoms and 2 non-hydrogen substituents; wherein n is 0 if W is a ring system (E); and pharmaceutically acceptable salts.

One embodiment of the invention provides a compound of formula Ib according to herein, wherein A ¹ is -CR ¹⁰ -; A ² is -O-; R ¹ is halogen or cyano; R ⁹ is H; R ² is alkyl And R ³ is H; R ⁸ is H; R ¹⁰ is H; n can be 0 or 1; W is selected from ring systems: (A), or (E), wherein, B ¹ is -CH-; B ² is -CHR ⁴ -; B ³ is -NR ⁶ - B ⁴ is -CH ₂ -; R ⁴ is H; R ⁶ is alkyl; having only up to 2 heteroatoms and 1 non-hydrogen substituent; wherein n is 0 if W is a ring system (E); and pharmaceutically acceptable salts.

One embodiment of the present invention provides a compound according to formula I, wherein the compound of formula I is a compound of formula Ib I

Compounds of formula I may contain several asymmetric centers and may be in the form of optically pure enantiomers, mixtures of enantiomers (e.g. racemates), optically pure diastereomers, diastereomers A mixture of diastereomeric racemates, a diastereomeric racemate, or a mixture of diastereomeric racemates.

Furthermore, one embodiment of the present invention provides the compound of formula I described herein and a pharmaceutically acceptable salt or ester thereof, specifically provides the compound of formula I described herein and its pharmaceutically acceptable salt, More particularly provided are compounds according to formula I as described herein.

One embodiment of the present invention provides a compound according to formula I described herein, wherein A ¹ is -N- or -CH-; A ² is -O-, -NH-, -NCH ₃ - or -S-; R ¹ is halogen, alkyl, haloalkyl or haloalkoxy; ^R is H, halogen or alkyl and R is H, halogen or alkyl, wherein at ^least one of R ^{and R} is not H; n can be 0 or 1; W is a heterocyclic ring optionally substituted with 1 to 2 substituents independently selected from the following: pendant oxy, -OH, alkyl, alkylamino, alkylamino Alkyl, amino, aminoalkyl, cycloalkyl, halogen-substituted cycloalkyl, dialkylamino, dialkylaminoalkyl, haloalkyl, hydroxyalkyl, and pyrrolidinylalkyl , or W is a 4- to 6-membered cycloalkyl optionally substituted with 1 to 2 substituents independently selected from the following: –OH, alkyl, alkylamine, amine, dialkylamine group, halogen, haloalkyl and tertiary butyl N-methylcarbamate; and pharmaceutically acceptable salts.

One embodiment of the present invention provides a compound according to formula I described herein, wherein A ¹ is -N- or -CH-; A ² is -O-, -NH-, -NCH ₃ - or -S-; R ¹ is halogen, alkyl, haloalkyl or haloalkoxy; ^R is H, halogen or alkyl and R is H, halogen or alkyl, wherein at ^least one of R ^{and R} is not H; n can be 0 or 1; W is the ring system (A), (B), or (C); B ¹ is -N- or -CH-; B ² is -CHR ⁴ - or -NCH ₃ ; B ³ is -CHR ⁵ -, -O- or -NR ⁶ - B ⁴ is -O-, -CH ₂ -, -NH-, -C(=O)-; B ⁵ is -CH-; B ⁶ is -NH-; B ⁷ is -CH ₂ -; B ⁸ is -N-; B ⁹ is - CH ₂ -; B ¹⁰ is -CHR ⁷ -; R ⁴ is H, dialkylaminoalkyl or hydroxyalkyl; R ⁵ is H, -OH, alkylamino, dialkylaminoalkyl or Hydroxyalkyl; R ⁶ is H or alkyl; R ⁷ is -OH; wherein W may only have up to 2 heteroatoms and 2 non-hydrogen substituents; wherein if W is a ring system C or B ¹ is -N- , then n is 0; and pharmaceutically acceptable salts.

One embodiment of the present invention provides a compound according to formula I described herein, wherein A ¹ is -CH-; A ² is -O- or -NH-; R ¹ is haloalkyl or halogen; R ² is alkyl and R ³ is H; n can be 0 or 1; W is a ring system (A), (B), or (C); B ¹ is -N- or -CH-; B ² is -CHR ⁴ - or -NCH ₃ ; B ³ is -CHR ⁵ -, -O- or -NR ⁶ - B ⁴ is -O-, -CH ₂ -, -NH-, -C(=O)-; B ⁵ is -CH-; B ⁶ is -NH-; B ⁷ is -CH ₂ -; B ⁸ is -N-; B ⁹ is - CH ₂ -; B ¹⁰ is -CHR ⁷ -; R ⁴ is H or dialkylaminoalkyl; R ⁵ is H, -OH, alkylamino or hydroxyalkyl; R ⁶ is H or alkyl; R ⁷ is -OH; wherein W may only have up to 2 heteroatoms and 2 non-hydrogen substituents; wherein if W is ring system C or B ¹ is -N-, then n is 0; and pharmaceutically acceptable Salt.

One embodiment of the present invention provides a compound according to formula I described herein, wherein A ¹ is -CH-; A ² is -O- or -NH-; R ¹ is haloalkyl or halogen; R ² is alkyl and R ³ is H; n can be 0 or 1; W is a ring system (A), (B), or (C); B ¹ is -N- or -CH-; B ² is -CHR ⁴ -; B ³ is -CHR ⁵ - or -NR ⁶ - B ⁴ is -O-, -CH ₂ -, -NH- , -C(=O)-; B ⁵ is -CH-; B ⁶ is -NH-; B ⁷ is -CH ₂ -; B ⁸ is -N-; B ⁹ is -CH ₂ -; B ¹⁰ is - CHR ⁷ -; R ⁴ is H or dialkylaminoalkyl; R ⁵ is H, -OH, alkylamino or hydroxyalkyl; R ⁶ is H or alkyl; R ⁷ is -OH; where W may have only up to 2 heteroatoms and 1 non-hydrogen substituent; wherein n is 0 if W is ring system C or B ¹ is -N-; and pharmaceutically acceptable salts.

One embodiment of the present invention provides a compound according to formula I described herein, wherein A ¹ is -CH-; A ² is -O- or -NH-; R ¹ is haloalkyl; R ² is alkyl and R ³ is H; n can be 0 or 1; W is a ring system (A), (B), or (C); B ¹ is -N- or -CH-; B ² is -CHR ⁴ -; B ³ is -CHR ⁵ - or -NR ⁶ - B ⁴ is -O-, -CH ₂ -, -NH- , -C(=O)-; B ⁵ is -CH-; B ⁶ is -NH-; B ⁷ is -CH ₂ -; B ⁸ is -N-; B ⁹ is -CH ₂ -; B ¹⁰ is - CHR ⁷ -; R ⁴ is H or dialkylaminoalkyl; R ⁵ is H, -OH, alkylamino or hydroxyalkyl; R ⁶ is H or alkyl; R ⁷ is -OH; where W may have only up to 2 heteroatoms and 1 non-hydrogen substituent; wherein n is 0 if W is ring system C or B ¹ is -N-; and pharmaceutically acceptable salts.

One embodiment of the present invention provides a compound according to formula I described herein, wherein A ¹ is -CH-; A ² is -O- or -NH-; R ¹ is haloalkyl; R ² is alkyl and R ³ is H; n can be 0 or 1; W is a ring system (A), or (B); B ¹ is -N- or -CH-; B ² is -CHR ⁴ -; B ³ is -CHR ⁵ - or -NR ⁶ - B ⁴ is -O-, -CH ₂ -, -NH- , -C(=O)-; B ⁵ is -CH-; B ⁶ is -NH-; B ⁷ is -CH ₂ -; R ⁴ is H or dialkylaminoalkyl; R ⁵ is H, - OH, alkylamino or hydroxyalkyl; R ⁶ is H or alkyl; wherein W can only have up to 2 heteroatoms and 1 non-hydrogen substituent; wherein if B ¹ is -N-, then n is 0 ; and pharmaceutically acceptable salts.

One embodiment of the present invention provides a compound according to formula I described herein, wherein A ¹ is -CH-; A ² is -O- or -NH-; R ¹ is haloalkyl; R ² is alkyl and R ³ is H; n can be 0 or 1; W is a ring system (A); B ¹ is -N- or -CH-; B ² is -CHR ⁴ -; B ³ is -CHR ⁵ - or -NR ⁶ - B ⁴ is -O- or -CH ₂ -; R ⁴ is H or dialkylaminoalkyl; R ⁵ is H; R ⁶ is alkyl; wherein W can only have up to 2 heteroatoms and 1 non-hydrogen substituent; wherein if B ¹ is -N-, then n is 0; and a pharmaceutically acceptable salt.

One embodiment of the invention provides a compound of formula I as described herein, wherein A ¹ is -CH-; A ² is -O-; R ¹ is haloalkyl; R ² is alkyl and R ³ is H; n is 1; W is the ring system (A); B ¹ is -CH-; B ² is -CHR ⁴ -; B ³ is -NR ⁶ - B ⁴ is -CH ₂ -; R ⁴ is H; R ⁶ is alkyl; and pharmaceutically acceptable of salt.

Specific examples of compounds of formula Ic as described herein are selected from 2-[2-[(3aS,7aR)-6-Methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]㗁Azolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol or 2-[2-[(3aR,7aS)-6-methyl-3, 3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl Base-5-(trifluoromethyl)phenol; 2-[2-[(3aR,7aS)-6-Methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]㗁Azolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol or 2-[2-[(3aS,7aR)-6-methyl-3, 3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl Base-5-(trifluoromethyl)phenol; (racemic)-3-methyl-2-[2-(tetrahydrofuran-3-ylamino)oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl) phenol; 5-Chloro-3-methyl-2-[2-[[rac-(8S,8aR)-1,2,3,5,6,7,8,8a-swainson-8-yl ]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[[(8S,8aR)-1,2,3,5,6,7,8,8a-swainson-8-yl]amino]oxazolo[4,5-b ]pyridin-5-yl]-5-chloro-3-methyl-phenol or 2-[2-[[(8R,8aS)-1,2,3,5,6,7,8,8a-octahydro Indolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 2-[2-[[(8R,8aS)-1,2,3,5,6,7,8,8a-swainson-8-yl]amino]oxazolo[4,5-b ]pyridin-5-yl]-5-chloro-3-methyl-phenol or 2-[2-[[(8S,8aR)-1,2,3,5,6,7,8,8a-octahydro Indolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 5-chloro-3-methyl-2-[2-(6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4 ](azin-4-yl)(oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-(2-Azabicyclo[2.1.1]hex-1-ylmethylamino)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5- (Trifluoromethyl)phenol; Dihydrochloride; 5-Chloro-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] phenol; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-fluoro-3-methyl -phenol; 5-Chloro-3-methyl-2-[2-[[(3R)-1-propyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] phenol; 5-Chloro-2-[2-[[(3R)-1-cyclobutyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl Base-phenol; 5-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3 - dihydrobenzofuran-4-ol; (3S,5R)-5-[[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1 -Methyl-piperidin-3-ol; 5-Fluoro-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] phenol; (3S,5R)-1-Ethyl-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine- 2-yl]amino]piperidin-3-ol; 2-[2-[[(3R)-1-(2-Hydroxyethyl)-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl Base-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-fluoro-5-(tri Fluoromethyl)phenol; 5-Chloro-2-[2-[[(3R,5S)-1-ethyl-5-fluoro-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-3-methyl-phenol; 2-[2-[[(1R,2R)-2-(Dimethylamino)cyclopropyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl -5-(trifluoromethyl)phenol; 3-Hydroxy-4-[2-[[(3R,5S)-5-hydroxy-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-5-methyl-benzonitrile; cis-2-[2-[(3-hydroxy-3-methyl-cyclobutyl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl- 5-(trifluoromethyl)phenol; trans-2-[2-[(3-Hydroxy-3-methyl-cyclobutyl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl- 5-(trifluoromethyl)phenol; 5-Chloro-2-[2-[(1-ethyltetrahydroazine-3-yl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl -phenol; 1-[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)-2-[[racemic-(3R)-1-methyl-3-piperidinyl]amino]㗁Azolo[4,5-b]pyridin-7-yl]pyrrolidin-2-one; 2-[2-[[(3R)-1-(3-Hydroxycyclobutyl)-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Methyl-5-(trifluoromethyl)phenol; 2-[2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)oxazolo[4,5-b]pyridin-5-yl ]-3-methyl-5-(trifluoromethyl)phenol; 5-Chloro-3-methyl-2-[2-[[(3R)-1-(oxetane-3-yl)-3-piperidinyl]amino]oxazolo[4,5 -b]pyridin-5-yl]phenol; 3-Methyl-2-[2-[rel-(4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4] Oxazin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid; 2-[2-[(4aS,7aS)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl] Zazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[(4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl] Zazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; N-(1,2,3,5,6,7,8,8a-swainson-6-yl)-5-chloro-oxazolo[4,5-b]pyridin-2-amine; 3-Methyl-2-[2-[[(2S)-1-methyltetrahydroazil-2-yl]methylamino]oxazolo[4,5-b]pyridin-5-yl] -5-(trifluoromethyl)phenol or 3-methyl-2-[2-[[(2R)-1-methyltetrahydroazine-2-yl]methylamino]oxazolo[4 ,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 3-Methyl-2-[2-[[(2R)-1-methyltetrahydroazia-2-yl]methylamino]oxazolo[4,5-b]pyridin-5-yl] -5-(trifluoromethyl)phenol or 3-methyl-2-[2-[[(2S)-1-methyltetrahydroazine-2-yl]methylamino]oxazolo[4 ,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 3-Methyl-2-[2-[(1-methyltetrahydroazine-2-yl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-5-( Trifluoromethyl)phenol; 5-Chloro-2-[2-(1H-imidazol-5-ylmethylamino)zozolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; (3RS,5R)-5-[[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1 -Ethyl-piperidin-3-ol; formic acid; 3,6-Dimethyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol ; (3R,5R)-5-[[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1 -Ethyl-piperidin-3-ol; formic acid; 4-[2-[[(3R,5R)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; 4-[2-[(3aS,7aR)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]㗁Azolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[(3aR,7aS)-6-ethyl-3,3a,4 ,5,7,7a-Hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxyl-5- Methyl-benzonitrile; 4-[2-[(3aR,7aS)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]㗁Azolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[(3aS,7aR)-6-ethyl-3,3a,4 ,5,7,7a-Hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxyl-5- Methyl-benzonitrile; 5-[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; (5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or ( 5R)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; (5R)-5-[5-(4-chloro-2-hydroxyl-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or ( 5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; 5-Chloro-2-[2-[[(3R)-1-(3,3-difluoropropyl)-3-piperidinyl]amino]oxazolo[4,5-b]pyridine-5 -yl]-3-methyl-phenol; 5-Chloro-3-methyl-2-[2-[[(3R)-1-[(3-hydroxycyclobutyl)methyl]-3-piperidinyl]amino]oxazolo[4, 5-b]pyridin-5-yl]phenol; 5-Chloro-2-[2-(1H-imidazol-2-ylmethylamino)zozolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 2-[2-[3-(Hydroxymethyl)-1-piperidinyl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl) phenol; 2-[2-[4-(Hydroxymethyl)-1-piperidinyl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl) phenol; 2-[2-(1-Ethyl-1,7-diazaspiro[3.5]non-7-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl- 5-(trifluoromethyl)phenol; 3-Hydroxy-5-methyl-4-[2-[racemic trans-6-ethyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][ 1,4]-oxazin-4-yl]oxazolo[4,5-b]pyridin-5-yl]benzonitrile; 3-Hydroxy-5-methyl-4-[2-(7-methyl-2,3,4,4a,5,6,8,8a-octahydro-1,7-phenidin-1-yl) Zazolo[4,5-b]pyridin-5-yl]benzonitrile; 2-Hydroxy-4-methyl-3-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] Benzonitrile; 2,2,2-trifluoroacetic acid; 5-Chloro-3-methyl-2-[2-[(1-methyl-3-piperidinyl)methyl]oxazolo[4,5-b]pyridin-5-yl]phenol; 4-[(3R)-3-[[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]- 1-piperidinyl]butyric acid methyl ester; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] -5-methyl-benzonitrile; 3-[(3R)-3-[[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]- Methyl 1-piperidinyl]propionate; 5-Chloro-2-[2-[[6-(hydroxymethyl)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]- 3-methyl-phenol; 2,2,2-trifluoroacetic acid; 5-Chloro-2-[2-[(4-isopropylmorpholin-2-yl)methyl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; formic acid; 3-Methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-methyl Sulfonyl-phenol; 2,2,2-trifluoroacetic acid; 5-Chloro-2-[2-[2-methoxyethyl-[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridine-5 -yl]-3-methyl-phenol; formic acid; 2-[2-[[(3R)-1-Ethylnitro-3-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-( Trifluoromethyl)phenol; 5-Chloro-2-[2-[(3-hydroxycyclobutyl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] -3-methyl-phenol; 5-Chloro-3-(hydroxymethyl)-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridine-5 -base] phenol; 5-Chloro-2-[2-[[(3R)-1-(3-hydroxypropyl)-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] -3-methyl-phenol; 5-Chloro-3-methyl-2-[2-[[rac-(3R)-1-(2-hydroxypropyl)-3-piperidinyl]amino]oxazolo[4,5 -b]pyridin-5-yl]phenol; 5-Chloro-2-[2-[2-hydroxyethyl-[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-3-methyl-phenol; 5-Chloro-2-[2-[[(3S,4R)-1-ethyl-4-fluoro-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-3-methyl-phenol; 5-Chloro-2-[2-[[(3R,4S)-1-ethyl-4-fluoro-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-3-methyl-phenol; (3S,5R)-5-[[5-[4-Chloro-2-hydroxy-6-(methoxymethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amine Base] -1-methyl-piperidin-3-ol; 1-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]-5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]㗁Azolo[4,5-b]pyridin-7-yl]tetrahydroacrin-3-ol; 1-[5-[2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-2-[[(3R)-1-methyl-3-piperidinyl]amino]㗁Azolo[4,5-b]pyridin-7-yl]ethanone; 2,2,2-trifluoroacetic acid; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]-7-(methylamino)oxazolo[4,5-b]pyridin-5-yl] -3-methyl-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3 - methyl-5-(trifluoromethyl)phenol; 2-[7-(1-Hydroxy-1-methyl-ethyl)-2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b ]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid; 2-[7-(1-Hydroxyethyl)-2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-3-methyl-5-(trifluoromethyl)phenol; 3-Chloro-4-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-hydroxy- Benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(1R,2R)-2-(Dimethylamino)cyclopentyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy- 5-methyl-benzonitrile; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methyl Base-benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxyl-5-(methyl oxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3 -Hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 5-Chloro-2-[2-[[(1R,2R)-2-(dimethylamino)cyclopentyl]amino]oxazolo[4,5-b]pyridin-5-yl]- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methanol Base-phenol; 2,2,2-trifluoroacetic acid; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(tri fluoromethoxy)phenol; 2,2,2-trifluoroacetic acid; 3-Hydroxy-5-methyl-4-[2-[[(2S)-2-hydroxy-1,2,3,5,6,7,8,8a-swainson-8-yl]amine Base] oxazolo[4,5-b]pyridin-5-yl]benzonitrile; 2,2,2-trifluoroacetic acid; 2-[7-(Dimethylamino)-2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-3-methyl-5-(trifluoromethyl)phenol; 2-[[(3R)-1-ethyl-3-piperidinyl]amino]-5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[ 4,5-b]pyridine-7-carbonitrile; 5-Chloro-2-[2-[[(3R)-1-[[racemic trans-2-hydroxycyclobutyl]methyl]-3-piperidinyl]amino]oxazolo[4 ,5-b]pyridin-5-yl]-3-methyl-phenol or 5-chloro-2-[2-[[(3R)-1-[[racemic cis-2-hydroxycyclobutyl ]methyl]-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-[[racemic trans-2-hydroxycyclobutyl]methyl]-3-piperidinyl]amino]oxazolo[4 ,5-b]pyridin-5-yl]-3-methyl-phenol or 5-chloro-2-[2-[[(3R)-1-[[racemic cis-2-hydroxycyclobutyl ]methyl]-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-benzonitrile; 3-methyl-2-[2-[(2-methyl-2-azabicyclo[2.2.2]oct-4-yl)amino]oxazolo[4,5-b]pyridine-5- Base] -5- (trifluoromethyl) phenol; 5-(Difluoromethyl)-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridine -5-yl]phenol; 5-(Difluoromethyl)-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] -3-methyl-phenol; 2,2,2-trifluoroacetic acid; 5-(Difluoromethyl)-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] -3-methyl-phenol; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3,5-dimethyl- phenol; 3-[[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-ethyl-piperidine -4-ol; 2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 5-fluoro-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(tri fluoromethyl)phenol; 2,2,2-trifluoroacetic acid; 5-Chloro-2-[6-chloro-2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol ; 3,5-Dimethyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol ; 2,2,2-trifluoroacetic acid; 3-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-fluoro- Phenol; 2,2,2-Trifluoroacetic acid; 5-(Difluoromethoxy)-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-3-methyl-phenol; 2,2,2-trifluoroacetic acid; 2-[2-[(1-Ethylpyrrolidin-3-yl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl )phenol; 3,5-dichloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 2,2,2-Trifluoroacetic acid; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-fluoro-1H-imidazo[4,5-b]pyridin-5-yl]-5- (Trifluoromethyl)phenol; (3S,5R)-5-[[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1 - Ethyl-piperidin-3-ol; 3-Methyl-2-[2-[4-(methylamino)tetrahydropyran-4-yl]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoro Methyl)phenol; 2,2,2-trifluoroacetic acid; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]-3H-imidazo[4,5-b]pyridin-5-yl]-3- Methyl-phenol; 2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-( trifluoromethoxy)phenol; 2,2,2-trifluoroacetic acid; 2-[2-(1-Ethyl-3-piperidinyl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 4-[2-[[(8R,8aR)-1,2,3,5,6,7,8,8a-swainson-8-yl]amino]oxazolo[4,5-b ]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[[(8S,8aS)-1,2,3,5,6,7,8,8a-octa Hydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(8S,8aS)-1,2,3,5,6,7,8,8a-swainson-8-yl]amino]oxazolo[4,5-b ]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[[(8R,8aR)-1,2,3,5,6,7,8,8a-octa Hydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; and its pharmaceutically acceptable salts.

Furthermore, specific examples of compounds of formula Ic as described herein are selected from (racemic)-2-[2-[(1-ethyl-3-piperidinyl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5 -(trifluoromethyl)phenol; (racemic)-2-[2-[3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3 - methyl-5-(trifluoromethyl)phenol; 2-[2-[(3R or 3S)-3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3 - methyl-5-(trifluoromethyl)phenol; 2-[2-[(3S or 3R)-3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3 - methyl-5-(trifluoromethyl)phenol; (racemic)-1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidine -3-ol; (3R or 3S)-1-[5-[2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidine -3-ol; (3S or 3R)-1-[5-[2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidine -3-ol; 3-Methyl-2-(2-morpholinyloxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; (racemic)-[2-[2-(Hydroxymethyl)morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(tri Fluoromethyl)phenol; 3-Methyl-2-(2-piperazin-1-yloxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-[2-[[3-(methylamino)cyclohexyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl )phenol; 3-methyl-2-(2-piperazin-1-yl-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; (racemic)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)oxazolo[4,5-b]pyridin-2-yl)piperidine -2-one; (racemic)-3-methyl-2-[2-[3-(methylamino)-1-piperidinyl]oxazolo[4,5-b]pyridin-5-yl]-5 -(trifluoromethyl)phenol; (racemic)-3-methyl-2-[2-(tetrahydropyran-3-ylamino)oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoro methyl) phenol; 1-[5-[2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]tetrahydroazia-3-ol ; 2-[2-[(3-Hydroxycyclohexyl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-( Trifluoromethyl)phenol; 3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-( Trifluoromethyl)phenol; (racemic)-3-methyl-2-(2-(1-methylpiperidin-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)-5-( Trifluoromethyl)phenol; (racemic)-3-methyl-2-(2-(pyrrolidin-2-yl)-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoro-methyl base) phenol; (racemic)-2-[2-[(1-ethyl-3-piperidinyl)amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl -5-(trifluoromethyl)phenol; 2-[2-[[(3R or 3S)-1-ethyl-3-piperidinyl]amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl -5-(trifluoromethyl)phenol; 2-[2-[[(3S or 3R)-1-ethyl-3-piperidinyl]amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl -5-(trifluoromethyl)phenol; and its pharmaceutically acceptable salts.

Furthermore, specific examples of compounds of formula Ic as described herein are selected from 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl -phenol; 5-Chloro-3-methyl-2-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1- base) oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[(3aS,7aR or 3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]zozolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 2-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]zozolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy- Benzonitrile; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methyl Oxymethyl) phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methyl Oxymethyl) phenol; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl - benzonitrile; 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] Benzonitrile; 4-[2-[(3aS,7aR or 3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; 4-[2-(1,2,3,5,6,7,8,8a-Swainson-8-ylamino)oxazolo[4,5-b]pyridin-5-yl]- 3-Hydroxy-5-methyl-benzonitrile; 3-(Difluoromethyl)-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] -5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-5- (Trifluoromethyl)phenol; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-5- (Trifluoromethyl)phenol; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-5- (Trifluoromethyl)phenol; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-5- (Trifluoromethyl)phenol; 2-[2-[(1-Ethyl-3-piperidinyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoroform base) phenol; 2-[2-[(1-Ethyl-3-piperidinyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoroform base) phenol; 3-Methyl-2-[7-methyl-2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-5-(trifluoromethyl)phenol; 3-Methyl-2-[7-methyl-2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-5-(trifluoromethyl)phenol; 5-Methoxy-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridine-5- Base] phenol; 5-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]-6-methyl-oxazolo[4,5-b]pyridin-5-yl]-2, 3-Dihydrobenzofuran-4-ol; 5-Cyclopropyl-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridine-5- Base] phenol; and its pharmaceutically acceptable salts.

Preferred examples of compounds of formula Ic as described herein are selected from 2-[2-[[(8R,8aS)-1,2,3,5,6,7,8,8a-swainson-8-yl]amino]oxazolo[4,5-b ]pyridin-5-yl]-5-chloro-3-methyl-phenol or 2-[2-[[(8S,8aR)-1,2,3,5,6,7,8,8a-octahydro Indolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 5-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3 - dihydrobenzofuran-4-ol; (3S,5R)-5-[[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1 -Methyl-piperidin-3-ol; 3-Hydroxy-4-[2-[[(3R,5S)-5-hydroxy-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-5-methyl-benzonitrile; 3-Methyl-2-[2-[rel-(4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4] Oxazin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid; (3R,5R)-5-[[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1 -Ethyl-piperidin-3-ol; formic acid; 4-[2-[[(3R,5R)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; 4-[2-[(3aS,7aR)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]㗁Azolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[(3aR,7aS)-6-ethyl-3,3a,4 ,5,7,7a-Hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxyl-5- Methyl-benzonitrile; (5R)-5-[5-(4-chloro-2-hydroxyl-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or ( 5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; 5-Chloro-3-methyl-2-[2-[(1-methyl-3-piperidinyl)methyl]oxazolo[4,5-b]pyridin-5-yl]phenol; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] -5-methyl-benzonitrile; 5-Chloro-2-[2-[[(3S,4R)-1-ethyl-4-fluoro-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-3-methyl-phenol; (3S,5R)-5-[[5-[4-Chloro-2-hydroxy-6-(methoxymethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amine Base] -1-methyl-piperidin-3-ol; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3 - methyl-5-(trifluoromethyl)phenol; 4-[2-[[(1R,2R)-2-(Dimethylamino)cyclopentyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy- 5-methyl-benzonitrile; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methyl Base-benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxyl-5-(methyl oxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3 -Hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 2-[[(3R)-1-ethyl-3-piperidinyl]amino]-5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[ 4,5-b]pyridine-7-carbonitrile; 5-(Difluoromethyl)-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridine -5-yl]phenol; 5-(Difluoromethyl)-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] -3-methyl-phenol; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3,5-dimethyl- phenol; 4-[2-[[(8S,8aS)-1,2,3,5,6,7,8,8a-swainson-8-yl]amino]oxazolo[4,5-b ]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[[(8R,8aR)-1,2,3,5,6,7,8,8a-octa Hydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; and its pharmaceutically acceptable salts.

More preferred examples of compounds of formula Ic as described herein are selected from 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl -phenol; 5-Chloro-3-methyl-2-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1- base) oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]zozolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl - benzonitrile; 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] Benzonitrile; 4-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; 2-[2-[(1-Ethyl-3-piperidinyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoroform base) phenol; 2-[2-[(1-Ethyl-3-piperidinyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoroform base) phenol; and its pharmaceutically acceptable salts.

A preferred example of a compound of formula Ic as described herein is selected from 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl - benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; formate; (5R)-5-[5-(4-chloro-2-hydroxyl-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or ( 5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methyl Base-benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxyl-5-(methyl oxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3 -Hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; and its pharmaceutically acceptable salts.

Furthermore, the best examples of compounds of formula Ic as described herein are selected from 4-[2-[[(3R,5R)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; (5R)-5-[5-(4-chloro-2-hydroxyl-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or ( 5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methyl Base-benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxyl-5-(methyl oxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid; and its pharmaceutically acceptable salts.

Preferred examples of compounds of formula Ib as described herein are selected from (racemic)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)oxazolo[4,5-b]pyridin-2-yl)piperidine -2-one; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl -phenol; 5-Chloro-3-methyl-2-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1- base) oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]zozolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy- Benzonitrile; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methyl Oxymethyl) phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methyl Oxymethyl) phenol; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl - benzonitrile; 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] Benzonitrile; 4-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; 4-[2-(1,2,3,5,6,7,8,8a-Swainson-8-ylamino)oxazolo[4,5-b]pyridin-5-yl]- 3-Hydroxy-5-methyl-benzonitrile; 2-[2-[(1-Ethyl-3-piperidinyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoroform base) phenol; 2-[2-[(1-Ethyl-3-piperidinyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoroform base) phenol; 5-Methoxy-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridine-5- Base] phenol; and its pharmaceutically acceptable salts.

A preferred example of a compound of formula Ib as described herein is selected from 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl -phenol 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl -Benzonitrile 4-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile and its pharmaceutically acceptable salts.

Specific examples of compounds of formula I as described herein are selected from (racemic)-2-[2-[(1-ethyl-3-piperidinyl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5 -(trifluoromethyl)phenol; (racemic)-2-[2-[3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3 - methyl-5-(trifluoromethyl)phenol; 2-[2-[(3R or 3S)-3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3 - methyl-5-(trifluoromethyl)phenol; 2-[2-[(3S or 3R)-3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3 - methyl-5-(trifluoromethyl)phenol; (racemic)-1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidine -3-ol; (3R or 3S)-1-[5-[2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidine -3-ol; (3S or 3R)-1-[5-[2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidine -3-ol; 3-Methyl-2-(2-morpholinyloxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; (racemic)-[2-[2-(Hydroxymethyl)morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(tri Fluoromethyl)phenol; 3-Methyl-2-(2-piperazin-1-yloxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(2-piperazin-1-yloxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol formate; 3-Methyl-2-[2-[[3-(methylamino)cyclohexyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl )phenol; 3-methyl-2-(2-piperazin-1-yl-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(2-piperazin-1-yl-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; 2,2,2 -Trifluoroacetate; (racemic)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)oxazolo[4,5-b]pyridin-2-yl)piperidine -2-one; (racemic)-3-methyl-2-[2-[3-(methylamino)-1-piperidinyl]oxazolo[4,5-b]pyridin-5-yl]-5 -(trifluoromethyl)phenol; (racemic)-3-methyl-2-[2-(tetrahydropyran-3-ylamino)oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoro methyl) phenol; 1-[5-[2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]tetrahydroazia-3-ol ; 2-[2-[(3-Hydroxycyclohexyl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-( Trifluoromethyl)phenol; 3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-( Trifluoromethyl)phenol; (racemic)-3-methyl-2-(2-(1-methylpiperidin-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)-5-( Trifluoromethyl)phenol; (racemic)-3-methyl-2-(2-(pyrrolidin-2-yl)-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoro-methyl base) phenol; (racemic)-2-[2-[(1-ethyl-3-piperidinyl)amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl -5-(trifluoromethyl)phenol; 2-[2-[[(3R or 3S)-1-ethyl-3-piperidinyl]amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl -5-(trifluoromethyl)phenol; 2-[2-[[(3S or 3R)-1-ethyl-3-piperidinyl]amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl -5-(trifluoromethyl)phenol; and its pharmaceutically acceptable salts.

Preferred examples of compounds of formula I as described herein are selected from (racemic)-2-[2-[(1-ethyl-3-piperidinyl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5 -(trifluoromethyl)phenol; 2-[2-[(3S or 3R)-3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3 - methyl-5-(trifluoromethyl)phenol; (3S or 3R)-1-[5-[2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidine -3-ol; 3-Methyl-2-(2-morpholinyloxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; (racemic)-[2-[2-(Hydroxymethyl)morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(tri Fluoromethyl)phenol; 3-Methyl-2-(2-piperazin-1-yloxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(2-piperazin-1-yloxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol formate; 3-Methyl-2-[2-[[3-(methylamino)cyclohexyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl )phenol; (racemic)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)oxazolo[4,5-b]pyridin-2-yl)piperidine -2-one; (racemic)-3-methyl-2-[2-[3-(methylamino)-1-piperidinyl]oxazolo[4,5-b]pyridin-5-yl]-5 -(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-( Trifluoromethyl)phenol; 3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-( Trifluoromethyl)phenol; (racemic)-3-methyl-2-(2-(pyrrolidin-2-yl)-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoro-methyl base) phenol; 2-[2-[[(3S or 3R)-1-ethyl-3-piperidinyl]amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl -5-(trifluoromethyl)phenol; and its pharmaceutically acceptable salts.

More preferred examples of compounds of formula I as described herein are selected from 2-[2-[(3S or 3R)-3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3 - methyl-5-(trifluoromethyl)phenol; 3-Methyl-2-(2-morpholinyloxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-( Trifluoromethyl)phenol; 3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-( Trifluoromethyl)phenol; and its pharmaceutically acceptable salts.

The best examples of compounds of formula I as described herein are selected from 2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-( Trifluoromethyl)phenol; 3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-( Trifluoromethyl)phenol; and its pharmaceutically acceptable salts.

Processes for the manufacture of compounds of formula Ic as described herein are objects of the present invention.

The compounds of formula Ic and pharmaceutically acceptable salts thereof of the present invention can be prepared by methods known in the art, for example, by the methods described below, wherein the following scheme 1 comprises making the compound of formula II and the compound of formula Ic A reaction wherein R ¹ , R ² , R ³ , R ⁸ , R ⁹ , R ^x , A ¹ , W and n are as described herein, A ² =O or NH, and R =H. Scheme 1 : General procedure for the synthesis of Ic compounds where ^A = O or NH

An alternative for the preparation of compounds of formula Ic and pharmaceutically acceptable salts thereof is shown in Scheme 2 below, which comprises reacting compounds of formula II with compounds of formula Ic, wherein R ¹ , R ² , R ³ , R ⁸ , R ⁹ , R ^x , A ¹ , A ² and W are as described herein, and n is zero. Scheme 2 : General procedure for the synthesis of compounds outlined in Ic ; n=0

An alternative for the preparation of compounds of formula Ic and pharmaceutically acceptable salts thereof is shown in Scheme 3 below, which comprises reacting compounds of formula X with compounds of formula Ic, wherein R ¹ , R ² , R ³ , R ⁸ , R ⁹ , R ^x , n and W are as described herein, A ¹ is N, and A ² is O. Scheme 3 : General procedure for the synthesis of compounds outlined in Ic , where A ¹ =N; A ² =O General Synthetic Scheme

Compounds of formula Ic according to the invention can be prepared according to the process variants described below and Schemes 1 , 1a , 1b , 2 , 3 , 3a , 3b and 4 below. Furthermore, it will be apparent to those skilled in the art that the described sequence of transformations can be modified in various orders. These transformations may include, for example, protection/cleavage of protecting groups, Pd-catalyzed coupling, reductive amination, and/or nucleophilic substitution. Starting materials are commercially available or can be prepared according to methods known in the open art.

As shown in Scheme 1a , commercially available building blocks of formula II (wherein X is a halogen atom such as bromine, chlorine or iodine (more preferably chlorine or bromine)) can be submitted to the cyclization reaction, usually using 1,1 '-Carbonyldiimidazole (CDI) or similar reagents such as 1,1'-thiocarbonyldiimidazole or carbon disulfide, followed by addition of methyl iodide in the presence of a conventional inorganic base such as potassium carbonate or via a chlorinating agent such as POCl ₃ reactions to prepare compounds of general formula III or IV , respectively. These compounds can then undergo nucleophilic aromatic substitution in order to prepare compounds of formula V. The nucleophilic aromatic substitution is performed in the presence of an organic base such as N,N -diisopropylethylamine (DIEA) or trimethylamine, which are well known to those skilled in the art and/or are commercially available. suitable amines, such as but not limited to NR ^x -W, wherein W and R ^x have the meanings given in the claims of the present invention, and n is 1 or 0. Usually heat is used with 1,4-dioxane as solvent, but in some cases where higher temperatures are required, dimethylsulfoxide (DMSO), N,N -dimethyl-formamide (DMF) are used Or solvents such as N -methyl-2-pyrrolidine (NMP). Alternatively, the reaction can also be performed under microwave irradiation. Addition of the left side to compounds of general formula V to form compounds of formula VI using palladium-catalyzed type reactions such as Suzuki cross-coupling in the presence of a palladium catalyst and boronic acid or boropinnacolate according to standard conditions well known to those skilled in the art affords the general Final compound of formula Ic (depending on boronic acid or ester substitution). In the case of a methyl ether protecting group, it is cleaved in a final step, typically with boron tribromide ( _BBr3 ) in dichloromethane, to give compounds of general formula Ic . Specific examples are described in more detail for each of the following exemplary compounds. Scheme 1 : General procedure for the synthesis of Ic compounds where ^A = O or NH

The synthesis of the Ic compound of the present invention is carried out according to the general synthesis steps shown in Scheme 1 , wherein R' can be OH or -C(CH ₃ ) ₂ -, and R is a protecting group known to the skilled person, such as Me, SEM , benzyl or any other suitable protecting group for phenols (see eg Protective Groups in organic Synthesis by TW Greene and PGM). Scheme 1a : Modification of "NW" or "W", eg in case of Boc-protecting group (where A ² =O or NH)

Further, in case the amine ^NRx -W or W contains , for example, a tertiary -butoxycarbonyl ( BOC ) protecting group Va , an additional deprotection step uses TFA (trifluoroacetic acid ) or HCl in dioxane or at a later stage after the introduction of the left aryl ( Scheme 1a or 1b , VII ). The corresponding amine then undergoes reductive amination widely known to those skilled in the art in the presence of a reducing agent such as borohydride (more specifically, for example sodium triacetoxyborohydride or sodium cyanoborohydride ) in the presence of an acid (eg, acetic acid) or a buffer (such as sodium acetate) using an aldehyde or ketone to obtain a derivative of general formula V or the final compound Ic . Scheme 1b. Derivatization of NR ^x -W and W .

In the case of n = 0, commercially available building blocks of formula II (wherein X is a halogen atom such as bromine, chlorine or iodine (more preferably chlorine or bromine)) can be first prepared under standard amide coupling conditions Such as EDCI and HOBt or HATU or acyl chloride undergo acylation followed by cyclization using acidic conditions (e.g. polyphosphoric acid, Eaton's reagent) or via the Mitsunobu reaction (using DIAD and triphenylphosphine in THF or diethyl ether) to give Intermediates of general formula IX . Finally, the Suzuki reaction as described above affords compounds of general formula Ic . Scheme 2 : General procedure for the synthesis of compounds outlined in Ic ; n=0 Scheme 3 : General procedure for the synthesis of compounds outlined in Ic , where A ¹ =N; A ² =O

In the case of A ¹ =N, commercially available building blocks of formula X , in which chlorine and bromine can also be exchanged, can be reacted with benzyl alcohol in the presence of a strong base such as sodium hydride to give compounds of general formula XI . A suitable solvent is eg THF. In the next step, reaction with the corresponding isothiocyanate and a base (eg sodium hydride) affords compounds of general formula XII . Cyclization to intermediate XIII can be performed by addition of reagents such as tetrabutylammonium iodide and hydrogen peroxide. In the final step, a Suzuki cross-coupling in the presence of a palladium catalyst and boronic acid or boropinnacolate according to standard conditions well known to those skilled in the art affords the final compound of general formula Ic . General synthetic scheme of scheme 3a.Ic , wherein A ¹ =N

Compounds of general formula Ic (wherein A ¹ =N) can also be obtained following the sequence outlined above. Starting from analogous precursors XI , Suzuki cross-couplings under standard conditions in the presence of palladium catalysts and boronic acid or boropinnacolate afford intermediates XIV . After protection of the phenol with eg SEM using standard procedures known to those skilled in the art, compound XV undergoes a reaction with an isothiocyanate in the presence of a base such as sodium hydride to give intermediate XVI . Subsequent cleavage of the protecting group (SEM) under standard acidic conditions (eg TFA) affords XVII . In the final step, cyclization is accomplished as outlined above. Scheme 3b. Synthesis of isothiocyanates

The described isocyanates can be prepared by reacting primary amines of the general formula shown in Scheme 3b with thiophosgene under ice cooling. Suitable solvents for this reaction are eg DCM or DCE. Scheme 4 : General procedure for compounds outlined in Ic , where A ¹ =CR ¹⁰ , R ¹⁰ ≠H.

Starting from commercially available building block XVIII , the nitration is carried out in the presence of strong acids known to those skilled in the art, such as fuming nitric acid, where X is iodine or bromine, preferably iodine. Reaction with tin(II) chloride or iron(III) chloride in eg methanol affords the aniline XX . Cyclization was then achieved by addition of TCDI and heating. Reaction with chlorinating agents such as oxalyl chloride or POCl3 in eg DMF at elevated temperature affords the key intermediate XXII . The compound undergoes nucleophilic aromatic substitution in the presence of organic bases such as N,N -diisopropylethylamine (DIEA) or trimethylamine, commonly used and/or known and/or commercially available to those skilled in the art Suitable amines NH-W or W-containing secondary amines or ^NRx -W proceed, where W and ^Rx have the meanings given for the general formula Ic . Typically 1,4-dioxane is used as solvent, but solvents such as dimethylsulfoxide (DMSO) or N -methyl-2-pyrrolidine (NMP) are also suitable. The different substituents outlined for R ¹⁰ in the claims and exemplified below are introduced in different ways, using palladium-catalyzed coupling reactions, for example in the presence of amides, carbonates or amines with corresponding ligands known to those skilled in the art Perform a Buchwald reaction, or use an organotin reagent for a Stille coupling or other suitable cross-coupling reaction. In the final step, a Suzuki reaction is performed to install the left side shown in general formula Ic . Scheme 4a : Alternative general route to compounds outlined in Ic , wherein A ¹ =CR ¹⁰ , R ¹⁰ ≠H.

An alternative to the modification described for R ¹⁰ starting from intermediate VI is outlined in Scheme 4a . Oxidation of the pyridinic nitrogen was achieved in the presence of methyl trioxyrhenium(vii) and in the presence of hydrogen peroxide. Subsequent introduction of X = Cl or Br is obtained by addition of a suitable halogenating reagent such as oxalyl chloride in, for example, DMF. The introduction of ^R10 was achieved using a Pd-catalyzed cross-coupling reaction or nucleophilic aromatic substitution. Finally, cleavage of the Boc protecting group under acidic conditions and reductive amination as outlined above affords the final compound Ic . Scheme 4b : Alternative route to compounds outlined in Ic , where A ¹ =CR ¹⁰ , R ¹⁰ ≠H.

Starting from building block XXVIII , the halogenation ( XXIX ) is carried out in the presence of N -bromosuccinimide (NBS) or bromine in solvents known to those skilled in the art, such as DMF. Subsequent Suzuki reaction with the corresponding boronic acid or boronic acid ester and reduction of the nitro group using eg palladium on carbon or iron or iron(III) chloride in a suitable solvent such as methanol affords intermediate XXXI . Finally, cyclization using TCDI followed by methylation with, for example, methyl iodide as detailed above, followed by nucleophilic aromatic substitution affords compounds of general formula IC where R ¹⁰ ≠ H.

Another embodiment of the invention provides pharmaceutical compositions or medicaments comprising the compounds of the invention and a therapeutically inert carrier, diluent or excipient, and methods of using the compounds of the invention for the preparation of such compositions and medicaments. In one example, a compound of formula Ib can be obtained by combining a compound of formula Ib at an appropriate pH at ambient temperature, and at a desired degree of purity, with a physiologically acceptable carrier (i.e., one that is nontoxic to recipients at the dosage and concentration employed). carrier) to be formulated into a galenical administration form. The pH of the formulation depends largely on the particular use and concentration of the compound, but in any case a preferred range is from about 3 to about 8. In one example, the compound of formula I is formulated in ethyl acetate buffer (pH 5). In another embodiment, the compound of Formula Ib is sterile. Compounds can be stored, for example, as a solid or amorphous composition, as a lyophilized preparation, or as an aqueous solution.

The compositions will be formulated, dosed and administered in a manner consistent with good medical practice. Factors considered in this context include the particular disease being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disease, the site of delivery of the agent, the method of administration, the schedule of administration, and others known to medical practitioners. factor.

The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, Intrathecal and epidural and intranasal, and, if desired, for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

The compounds of the present invention may be administered in any convenient administration form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. These compositions may contain conventional ingredients in pharmaceutical preparations, such as diluents, carriers, pH regulators, sweeteners, fillers and other active agents.

Typical formulations are prepared by admixing a compound of the invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients.Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, penetrants, glidants, processing aids, colorants, Sweeteners, flavoring agents, flavoring agents, diluents, and other known additives provide good presentation of drugs (ie, compounds of the present invention or pharmaceutical compositions thereof) or aid in the manufacture of drugs (ie, medicaments).

Compounds of formula Ic and pharmaceutically acceptable salts thereof can be processed together with pharmaceutically inert, inorganic or organic adjuvants for the manufacture of tablets, coated tablets, dragees, hard gelatin capsules, injection solutions or topical formulations. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. are used as such adjuvants for tablets, dragees and hard gelatin capsules.

Compounds of formula Ib and pharmaceutically acceptable salts thereof can be processed together with pharmaceutically inert, inorganic or organic adjuvants for the manufacture of tablets, coated tablets, dragees, hard gelatin capsules, injection solutions or topical formulations. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. are used as such adjuvants for tablets, dragees and hard gelatine capsules.

Compounds of formula I and pharmaceutically acceptable salts thereof can be processed together with pharmaceutically inert, inorganic or organic adjuvants for the manufacture of tablets, coated tablets, dragees, hard gelatin capsules, injection solutions or topical formulations, which can be For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. are used as such adjuvants for tablets, dragees and hard gelatine capsules.

Suitable adjuvants for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols and the like.

Suitable adjuvants for producing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, dextrose and the like.

Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

Suitable adjuvants for topical ophthalmic formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.

In addition, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying the osmotic pressure, buffers, masking agents or Antioxidants. They may also contain other therapeutically valuable substances.

The dosage may vary within wide limits and will, of course, be adapted to the individual requirements of each particular case. In general, in the case of oral administration, a daily dose of about 0.1 mg to 20 mg/kg body weight, preferably about 0.5 mg to 4 mg/kg body weight (eg about 300 mg per person) is preferably divided into 1 Up to 3 separate doses (which may consist, for example, of the same amount) should be appropriate. In case of topical administration, the formulation may contain drug at 0.001% to 15% by weight and the required dose may be between 0.1 and 25 mg. The desired dose may be administered in a single daily or weekly dose, or in multiple daily doses (2 to 4 doses), or multiple weekly doses, however, it will be apparent that the upper or lower limits given herein may be exceeded when indicated.

One embodiment of the invention is a compound according to formula Ic as described herein for use as a therapeutically active substance.

One embodiment of the invention is a compound according to formula Ic as described herein for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

One embodiment of the invention is a compound according to formula Ic as described herein for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

One embodiment of the invention is a compound according to formula Ib as described herein for use as a therapeutically active substance.

One embodiment of the invention is a compound according to formula Ib as described herein for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

One embodiment of the invention is a compound according to formula Ib as described herein for use in the treatment or prophylaxis of a disease, disorder or condition, wherein the disorder or condition is responsive to NLRP3 inhibition.

One embodiment of the invention is a compound according to formula I as described herein for use as a therapeutically active substance.

One embodiment of the invention is a compound according to formula I as described herein for use in the treatment or prophylaxis of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

One embodiment of the invention is a compound according to formula I as described herein for use in the treatment or prophylaxis of a disease, disorder or condition, wherein the disorder or condition is responsive to NLRP3 inhibition.

As used herein, the term "NLRP3 inhibition" refers to a complete or partial decrease in the level of NLRP3 activity and includes, for example, inhibition of active NLRP3 and/or inhibition of activation of NLRP3.

Evidence suggests a role for IL-1 and IL-18 induced by NLRP3 in inflammatory responses that occur in association with or result from a variety of different abnormalities (Menu et al ., Clinical and Experimental Immunology, 166:1-15, 2011; Strowig et al. , Nature, 481:278-286, 2012).

In one embodiment, the disease, disorder or condition is selected from: (i) inflammation; (ii) Autoimmune diseases; (iii) cancer; (iv) infection; (v) diseases of the central nervous system; (vi) metabolic diseases; (vii) cardiovascular disease; (viii) respiratory diseases; (ix) liver disease; (x) kidney disease; (xi) eye diseases; (xii) skin diseases; (xiii) lymphatic conditions; (xiv) mental illness; (xv) Graft versus host disease; (xvi) Painful to light touch; (xvii) conditions associated with diabetes; and (xviii) Any disease in an individual identified as having a germline or somatic non-silent mutation of NLRP3.

In another embodiment, the disease, disorder or condition is selected from: (i) cancer; (ii) infection; (iii) diseases of the central nervous system; (iv) cardiovascular disease; (v) liver disease; (vi) eye disease; or (vii) Skin diseases.

In another exemplary embodiment of the invention, the disease, disorder or condition is inflammation. Examples of inflammation that may be treated or prevented include inflammatory reactions that occur in connection with or result from: (i) Skin conditions such as contact allergy, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus , scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema or alopecia; (ii) Joint disorders such as osteoarthritis, systemic juvenile idiopathic arthritis, adult Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, gout, or seronegative spondyloarthritis Lesions (such as adhesive spondylitis, psoriatic arthritis, or Reiter's disease); (iii) muscle disorders such as polymyositis or myasthenia gravis; (iv) Gastrointestinal disorders such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), colitis, gastric ulcer, celiac disease, proctitis, pancreatitis, eosinophilic gastroenteritis , adipocytosis, antiphospholipid syndrome, or food-related allergies that may have far-reaching effects in the gut (for example, migraine, rhinitis, or eczema); (v) respiratory conditions such as chronic obstructive pulmonary disease (COPD), asthma (including eosinophilic, bronchial, allergic, intrinsic, extrinsic or dust asthma, and in particular chronic or persistent refractory asthma, such as advanced asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, pumlenta rhinitis (rhinitis pumlenta), dry rhinitis, drug-induced Rhinitis, membranous rhinitis, seasonal rhinitis such as hay fever and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, volcanic ash-induced inflammation , adult respiratory distress syndrome, hypersensitivity pneumonitis or idiopathic interstitial pneumonia; (vi) Vascular disorders such as atherosclerosis, Behcet's disease, vasculitis, or Wegener's granulomatosis; (vii) Autoimmune conditions such as systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type 1 diabetes, idiopathic thrombocytopenic purpura Syndrome or Graves disease; (viii) Eye disorders such as uveitis, allergic conjunctivitis or vernal conjunctivitis; (ix) neurological disorders such as multiple sclerosis or encephalomyelitis; (x) Infections or infection-related conditions, such as acquired immunodeficiency syndrome (AIDS), acute or chronic bacterial infections, acute or chronic parasitic infections, acute or chronic viral infections, acute or chronic fungal infections, meningitis, hepatitis (A type B or C or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, kala-azar, streptococcal myositis, Mycobacterium tuberculosis (including Mycobacterium tuberculosis and HIV co-infection ), Mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, orchitis/epididymitis, Legionella, Lyme disease, Influenza A, Estin-Barr virus infection, viral encephalitis / Aseptic meningitis or pelvic inflammatory disease; (xi) Renal disorders such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, obesity-related glomerulopathy, acute renal failure, acute kidney injury, Uremia, renal syndrome, renal fibrosis (including chronic crystal nephropathy), or renal hypertension; (xii) lymphatic disorders such as Castleman's disease; (xiii) Immune system disorders or disorders involving the immune system, such as hyper-IgE syndrome, neoplastic leprosy, familial phagocytic hemocytic lymphohistiocytosis, or graft-versus-host disease; (xiv) Liver disorders such as chronic active hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), Alcoholic steatohepatitis (ASH), primary biliary cirrhosis, fulminant hepatitis, liver fibrosis, or liver failure; (xv) Cancer, including those listed above; (xvi) burns, wounds, trauma, bleeding or stroke; (xvii) radiation exposure; (xviii) metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout or pseudogout; and/or (xix) Pain such as inflammatory hyperalgesia, pelvic pain, tenderness to light touch, neuropathic pain, or cancer-induced bone pain.

One embodiment of the invention is a compound according to formula Ic as described herein for use in the treatment or prevention of a disease, disorder or condition selected from: (i) inflammation; (ii) autoimmune diseases; (iii) cancer; (iv) infection; (v) central nervous system disorders; (vi) metabolic diseases; (vii) cardiovascular disease; (viii) respiratory diseases; (ix) liver disease; (x) kidney disease; (xi) eye diseases; (xii) skin diseases; (xiii) lymphatic conditions; (xiv) mental illness; (xv) Graft versus host disease; (xvi) tenderness to light touch; (xvii) Diabetes-related conditions; and (xviii) Any disease in an individual identified as having a germline or somatic non-silent mutation of NLRP3.

One embodiment of the invention is the use of a compound according to formula Ic as described herein for the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

One embodiment of the invention is the use of a compound according to formula Ic as described herein in the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

One embodiment of the invention is the use of a compound according to formula Ic as described herein in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

One embodiment of the present invention is according to the compound of formula Ic as described herein in the treatment or prevention of a disease, disorder or Use in medical conditions.

One embodiment of the invention is a compound according to formula Ic as described herein for use in the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

One embodiment of the invention is a compound according to formula Ic as described herein for use in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

One embodiment of the invention is a compound according to formula Ic as described herein for use in the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases including Crohn's disease and ulcerative colitis .

One embodiment of the present invention is the use of a compound according to formula Ic as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

One embodiment of the invention is the use of a compound according to formula Ic as described herein for the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

One embodiment of the present invention is the use of a compound of formula Ic as described herein for the preparation of a medicament for the treatment or prevention of inflammatory bowel diseases (including Crohn's disease and ulcerative colitis) ) disease, disease or condition.

One embodiment of the invention is a method of treating or preventing a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease, the method comprising administering an effective amount of a compound according to formula Ic as described herein .

One embodiment of the invention is a method of treating or preventing a disease, disorder or condition selected from asthma or COPD, the method comprising administering an effective amount of a compound according to formula Ic as described herein.

One embodiment of the invention is a method of treating or preventing a disease, disorder or condition selected from inflammatory bowel disease (including Crohn's disease and ulcerative colitis), the method comprising administering an effective amount according to Compounds of Formula Ic described herein.

One embodiment of the invention is directed to a method of inhibiting NLRP3 comprising administering an effective amount of a compound according to Formula Ic as described herein.

Furthermore, an embodiment of the invention is a compound of formula Ic as described herein made according to any of the methods.

One embodiment of the invention is a pharmaceutical composition comprising a compound according to formula Ic as described herein and a therapeutically inert carrier.

One embodiment of the invention is the use of a compound according to formula Ib as described herein for the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

One embodiment of the invention is the use of a compound according to formula Ib as described herein in the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease (Parkinson's disease).

One embodiment of the invention is the use of a compound according to formula Ib as described herein in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

One embodiment of the present invention is the use of a compound according to formula Ib as described herein in the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases including Crohn's disease and ulcerative colitis .

One embodiment of the invention is a compound according to formula Ib as described herein for use in the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

One embodiment of the invention is a compound according to formula Ib as described herein for use in the treatment or prophylaxis of a disease, disorder or condition selected from asthma or COPD.

One embodiment of the invention is a compound according to formula Ib as described herein for use in the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases including Crohn's disease and ulcerative colitis .

One embodiment of the present invention is the use of a compound according to formula Ib as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

One embodiment of the invention is the use of a compound according to formula Ib as described herein for the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

One embodiment of the present invention is according to the compound of formula Ib as described herein in the preparation for the treatment or prevention of a disease, abnormality or condition selected from inflammatory bowel disease (including Crohn's disease and ulcerative colitis) use in medicines.

One embodiment of the invention is a method of treating or preventing a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease, the method comprising administering an effective amount of a compound according to formula Ib as described herein .

One embodiment of the invention is a method of treating or preventing a disease, disorder or condition selected from asthma or COPD, the method comprising administering an effective amount of a compound according to Formula Ib as described herein.

One embodiment of the invention is a method of treating or preventing a disease, disorder or condition selected from inflammatory bowel disease (including Crohn's disease and ulcerative colitis), the method comprising administering an effective amount according to Compounds of formula Ib described herein.

One embodiment of the invention is directed to a method of inhibiting NLRP3 comprising administering an effective amount of a compound according to Formula Ib as described herein.

Furthermore, an embodiment of the invention is a compound of formula Ib as described herein made according to any of the methods.

One embodiment of the invention is a pharmaceutical composition comprising a compound according to formula Ib as described herein and a therapeutically inert carrier.

One embodiment of the invention is the use of a compound according to formula I as described herein for the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

One embodiment of the invention is the use of a compound according to formula I as described herein in the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

One embodiment of the invention is the use of a compound according to formula I as described herein in the treatment or prophylaxis of a disease, disorder or condition selected from asthma or COPD.

One embodiment of the present invention is the use of a compound according to formula I as described herein in the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases including Crohn's disease and ulcerative colitis .

One embodiment of the invention is a compound according to formula I as described herein for use in the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

One embodiment of the invention is a compound according to formula I as described herein for use in the treatment or prophylaxis of a disease, disorder or condition selected from asthma or COPD.

One embodiment of the invention is a compound according to formula I as described herein for use in the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases including Crohn's disease and ulcerative colitis .

One embodiment of the present invention is the use of a compound of formula I as described herein for the preparation of a medicament for the treatment or prevention of a disease, abnormality or condition selected from Alzheimer's disease and Parkinson's disease .

One embodiment of the present invention is the use of a compound of formula I as described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

One embodiment of the present invention is the use of a compound of formula I as described herein for the preparation of a medicament for the treatment or prevention of inflammatory bowel diseases (including Crohn's disease and ulcerative colitis) ) disease, disease or condition.

One embodiment of the invention is a method of treating or preventing a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease, the method comprising administering an effective amount of a compound according to formula I as described herein .

One embodiment of the invention is a method of treating or preventing a disease, disorder or condition selected from asthma or COPD, the method comprising administering an effective amount of a compound according to formula I as described herein.

One embodiment of the invention is a method of treating or preventing a disease, disorder or condition selected from inflammatory bowel disease (including Crohn's disease and ulcerative colitis), the method comprising administering an effective amount according to Compounds of formula I described herein.

One embodiment of the invention relates to a method of inhibiting NLRP3 comprising administering an effective amount of a compound according to formula I as described herein.

Furthermore, an embodiment of the invention is a compound of formula I as described herein, produced according to any of the methods.

One embodiment of the invention is a pharmaceutical composition comprising a compound according to formula I as described herein and a therapeutically inert carrier. Assay Procedures for NLRP3 and Pyroptosis

Activation of NLRP3 is known to lead to pyroptosis, and this feature plays an important role in clinical disease manifestations (Yan-gang Liu et al ., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al. , Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al ., Journal of Medicinal Chemistry, 2016, 59(5), 1691-1710; Ema Ozaki et al. , Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie and Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia Cocco et al. , Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al. , Cell Death & Disease, 2013, 4, e644). Therefore, inhibitors of NLRP3 are expected to block pyroptosis and the release of pro-inflammatory cytokines such as IL-1β from cells. THP-1 cells: culture and preparation

THP-1 cells (ATCC # TIB-202) were cultured in 1 mM sodium pyruvate (Sigma # S8636) and Penicillin (100 units/ml)/Streptomycin (0.1mg/ml) (Sigma # P4333) in RPMI. Cells were routinely passaged and grown to confluence (approximately ¹⁰⁶ cells/ml). On the day of the experiment, THP-1 cells were harvested and resuspended in RPMI medium (without FBS). Cells were then counted and checked for viability (>90%) by trypan blue (Sigma # T8154). Appropriate dilutions were made to obtain a concentration of 625,000 cells/ml. To this diluted cell solution was added LPS (Sigma # L4524) to give a final assay concentration (FAC) of 1 µg/ml. Aliquot 40 µl of the final preparation into wells of a 96-well plate. The plates thus prepared were used for compound screening. THP-1 cell pyroptosis assay

Compound screening was carried out step by step according to the following method. 1. Seed THP-1 cells (25,000 cells/well) in 40 μl RPMI medium (without FBS) containing 1.0 μg/ml LPS in poly-D-lysine-coated 96-well, black wall, clear bottom cell culture dish (VWR # 734-0317) 2. Add 5 µl of compound (8-point semi-log dilution, up to 10 µM) or vehicle (DMSO 0.1% FAC) to appropriate wells 3. At 37 Incubate at 5% CO _for 3 hours at °C 4. Add 5 µl of nigericin (Sigma # N7143) (FAC 5 µM) to all wells 5. Incubate for ₁ hour at 37°C with 5% CO 6. Incubation period At the end, centrifuge the plate at 300xg for 3 min and remove the supernatant 7. Then add 50 µl resazurin (Sigma # R7017) (FAC 100 µM resazurin in RPMI medium without FBS) and place the plate in Incubate further for 1 to ₂ hours at 37°C and 5% CO 8. Read plate on Envision microplate reader at Ex 560nm and Em 590nm 9. Fit _IC50 data to non-linear regression equation (log(inhibitor) vs. response - variable slope 4 parameters)

The results of the pyroptosis assay are summarized in Table 1 below as THP _IC50 . Human Whole Blood IL-1β Release Assay

For systemic delivery, the ability of a compound to inhibit NLRP3 when it is present in the bloodstream has important implications. For this reason, the NLRP3 inhibitory activity of a number of compounds in human whole blood was studied according to the following protocol.

Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel. 1. Plate 80µl of whole blood containing 1µg/ml LPS in a 96-well clear-bottomed cell culture dish (Corning # 3585) 2. Plate 10µl of compound (8-point half-log dilution, maximum dose 10µM) or vehicle (DMSO 0.1% FAC) to appropriate wells 3. Incubate for 3 hours at 37°C, 5% CO ₂ 4. Add 10 µl nigericin (Sigma # N7143) (10 µM FAC) to all wells 5. Incubate at 37°C, Incubate for 1 hour in 5% CO ₂ 6. At the end of the incubation period, centrifuge the plate at 300xg for 5 minutes to pellet the cells and remove 20 µl of the supernatant before adding to a 96-well V-bottom dish for IL-1β analysis (Note: These plates containing the supernatant can be stored at -80°C for later analysis) 7. Measure IL-1β according to manufacturer's protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000) 8. _IC50 Data fit to non-linear regression equation (log(inhibitor) vs. response - variable slope 4 parameters) Table 1 : NLRP3 inhibitory activity instance number IC ₅₀ (nM) of THP-1 cell pyroptosis assay 1 1.9 2 17.4 2A 128.6 2B 16.9 3 75.4 3A 75.0 3B 28.6 4 29.4 5 31.9 6 86.6 7 82.1 8 302.0 9 15.3 10 107.4 11 216.6 12 214.7 13 441.6 14 1.0 15 0.7 16 330.0 17 183.0 18A 4.1 18B 392.4 19 0.4 20 1.2 20A 148.5 20B 0.5 twenty one 0.6 twenty two 5.4 twenty three 4.2 twenty four 1.7 25 1.6 26 2.8 27A 578 27B 2.7 28 4.6 29 5.1 30 4.5 31 4.0 32 3.0 33 5.8 34 18.9 35 27.3 36 32.0 37B 1.1 37A 216.2 38 85.3 39 1.9 40 27.4 41 0.6 42 5.1 43 30.5 44 0.7 45 0.9 46 1.0 47 1.2 48 1.2 49 1.6 50 1.7 51 1.8 52 2.3 53 2.6 54 10.1 55 17.8 56 18.9 57 50.3 58 95.9 59 30.1 60 17.9 61 39.4 62 84.8 63 57.5 64 4.9 64B 13.9 64A 1.7 65 20.3 66B 256.2 66A 397.5 66 148.6 67 290.0 68 62.4 69 2.7 70 3.8 71 1.1 72A 1.0 72B 309.7 73 30.0 73B 78.7 73A 18.7 74 9.2 75 20.8 76 143.0 77 134.7 78 58.3 79 94.9 80 109.9 81 72.3 82 128.2 83 5.1 84 0.8 85 15.4 86 0.6 87 75.6 88 6.0 89 536.1 90 22.6 91 4.9 92 26.9 93 2.1 94 11.9 95 11.2 96 56.1 97 93.9 98 11.1 99A 1.9 99B 380 -> 1000 100 18.4 101 6.0 102 6.5 103 4.6 104 1.9 105 8.9 106 22.0 107 8.8 108 16.8 109 1.4 110 5.8 111 2.2 112 6.6 113 0.5 114 1.1 115 48.5 116 6.9 117 5.2 118A 50.8 118B 30.6 119 23.0 120 107.7 121 2.7 122 1.0 123 0.7 124 53.8 125 3.0 126 3.9 127 20.6 128 1.8 129 1.7 130 1.9 131 9.6 132 0.7 133 80.3 134 1.9 135 505.0 136 1.0 137 4.8 138 233.6 139B 59.9 139A 3.7

The invention will now be illustrated by the following examples without limiting character.

In cases where the prepared examples were obtained as mixtures of enantiomers or diastereoisomers, the pure enantiomers or diastereomers may be obtained by methods described herein or known to those skilled in the art. Such as chiral chromatography or crystallization to obtain. In some examples (eg, 99a and 99b), the absolute stereoconfiguration was not determined, but was assigned based on biological activity ( eg, determined in a THP assay). Experimental method abbreviation: Q Water-based DCM Dichloromethane DIPEA Diisopropylethylamine DMF N,N -Dimethylformamide hr(s), h(s) Hour HOB Hydroxybenzotriazole EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Methanesulfonate (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl- 2-yl)palladium(ii) XPhos Pd G3 rt, rt, rt room temperature tBME, MTBE Methyl tertiary butyl ether Preparative HPLC Preparative HPLC TFA Trifluoroacetate T ₃ P Propylphosphonic anhydride MeCN Acetonitrile Sat saturation Analytical method

NMR spectra were run on a Bruker 400 MHz spectrometer using ICON-NMR under the control of the TopSpin program. Spectra were measured at 298 K and referenced to solvent resonance unless otherwise stated. LC-MS method:

Use SHIMADZU LCMS-2020, Agilent 1200 LC/G1956A MSD and Agilent 1200\G6110A, Agilent 1200 LC and Agilent 6110 MSD. Mobile phase: A: 0.025% NH3·H2O in water (v/v); B: acetonitrile. Column: Kinetex EVO C18 2.1 × 30 mm, 5um. System Waters Acquity UPLC - Binary pump - Autosampler Waters 2777C (alias CTC Pal HT) - Column manager (4 columns) - Photodiode array detector (PDA) - Single quadrupole mass spectrometer (respectively For SQD1 and SQD2) eluent channel A: water 0.1% formic acid channel B: acetonitrile 0.07% formic acid built-in column ( at 50°C) : column 1: Agilent Zorbax Eclipse Plus C18 rapid separation HT column, 2.1 × 30 mm, 1.8 µm, p/n 959731-902 Column 2: (MS1+5+7 only): Waters Acquity UPLC BEH C18, 2.1 × 50 mm, 1.7 µm, p/n 186002350 Column 3: None Column 4: None (Flow injection) method: Fast gradient (2 minutes, column 1, mass range m/z 150 to 900) time (min) Flow rate (ml/min) %A %B initial 0.8 97 3 0.2 1.0 97 3 1.7 1.0 3 97 2.0 1.0 3 97 2.1 1.0 97 3 Purification method ( step B)

Automated reverse-phase column chromatography was performed using a Gilson GX-281 system driven by a Gilson-322 pump module, a Gilson-156 UV photometer detection unit, and a Gilson-281 fraction collector. Waters Xbridge: 150 × 25 mm × 5 um pH (Water (10 mM NH ₃ H ₂ O)-ACN) 7 to 8 Average particle size: 5µm

Before use, condition the column with 100% MeCN (2 minutes) and then add 1% MeCN (0.8 minutes). Flow rate = 25 mL/min. Separate run: time (min) A : Water ₍ 10 mM _NH3H2O ) B MeCN 0 82% 18% 1.0 82% 18% 10.0 52% 48% 10.2 0% 100% 12.0 0% 100% 12.2 95% 5% 13.0 95% 5%

Detection wavelength: 220 nm and 254 nm. Before each new run, purge the cassette using the conditioning method. General Procedure: GP1 : Aromatic Nucleophilic Substitution

To 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS # 1783370-92-2, 1.00 eq) in 1,4-dioxane (0.5 mmol/mL) To the mixture was added the corresponding amine (1.16 eq) followed by triethylamine (1.14 eq). The solution was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture is extracted with a suitable organic solvent such as ethyl acetate, and the organic phase is washed with eg saturated aqueous NaHCO3. The combined organic layers are dried eg over sodium sulfate, filtered and concentrated in vacuo and finally purified via column chromatography or HPLC. GP2 : Suzuki 2a: with dppf

5-Chloro-N-[(3R)-1-ethyl-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine (1.0 eq) with the corresponding boronic acid or boronate (1.4 to 1.7 eq), potassium carbonate (4.8 eq), and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(ii) dichloromethane complex (0.15 eq) dissolved in 1,4-dioxane (0.1067 mmol/mL) and water (0.1067 mmol/mL, v/v 2/1), and the mixture was flushed with argon and stirred at 95 °C until the starting material was consumed (Most take 8 to 16 hours). After cooling to room temperature, the mixture is extracted with a suitable organic solvent such as ethyl acetate, and the organic phase is washed with eg half-saturated aqueous NH4Cl. The combined organic layers are dried eg over sodium sulfate, filtered and concentrated in vacuo and finally purified via column chromatography or HPLC. 2b. with Xphos

5-Chloro-N-[(3R)-1-ethyl-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine (1.00 eq) with the corresponding boronic acid or boronate (1.4 to 1.7 eq), a mixture of cesium carbonate (3.0 eq) and XPhos Pd G3 (0.1 eq) was dissolved in 1,4-dioxane and water (v/v 4/1), and the mixture was purged with argon Rinse and stir at 90°C until starting material is consumed. After cooling to room temperature, the mixture is extracted with a suitable organic solvent such as ethyl acetate and the organic phase is washed eg with brine. The combined organic layers are dried eg over sodium sulfate, filtered and concentrated in vacuo and finally purified via column chromatography or HPLC. GP3 : boc deprotection with TFA

The corresponding tert-butyl carboxylate (1.0 eq) was treated with TFA in dichloromethane (9.0 eq) and the reaction was stirred at room temperature until the starting material was consumed. The solvent was then removed under reduced pressure. GP4 : Reductive Amination

To a suspension of the corresponding primary or secondary amine (free base; HCl or TFA salt) (1.0 eq) in anhydrous DCM (0.0702 mmol/mL) was added acetaldehyde (2.5 eq) under ice-bath cooling, Sodium acetate (2.5 eq) was then added. Then, sodium triacetyloxyborohydride (1.8 eq) was added at 0 °C. The reaction mixture was stirred at 0 °C for 5 min, then the ice bath was removed and stirred at 23 °C for 3 to 5 h. The reaction mixture is then carefully basified with eg aqueous NaHCO3 under ice cooling and then extracted with a suitable organic solvent such as dichloromethane. The combined organic layers are dried eg over sodium sulfate, filtered and concentrated in vacuo and finally purified via column chromatography or HPLC.

In some cases, a mixture of DCM/MeOH was used as solvent. example

All examples and intermediates were prepared under nitrogen if not stated otherwise. Example 1 : ( racemic )-2-[2-[(1- ethyl -3- piperidinyl ) amino ] oxazolo [4,5- b ] pyridin -5- yl ]-3- methyl Base -5-( trifluoromethyl ) phenol

step 1 : ( Racemization )-5- chlorine - N -(1- Ethyl -3- piperidinyl ) zozolo [4,5- b ] pyridine -2- amine

To 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 80 mg, 0.379 mmol, 1 eq) in 1,4-dioxane ( (0.80 mL) was added ( racemic )-(1-ethyl-3-piperidinyl)amine (CAS # 6789-94-2, 0.061 mL, 0.427 mmol, 1.13 eq) followed by triethyl Amine (0.060 mL, 0.430 mmol, 1.14 eq). The brown solution was stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated aqueous NaHCO ₃ . The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 12 g, gradient: 0% to 10% methanol in dichloromethane) to afford the title compound (96 mg, 86% yield) as a pale yellow oil. LCMS: m / z 281.3 [M+H]+, ESI pos.

step 2 : ( Racemization )-2-[2-[(1- Ethyl -3- piperidinyl ) Amino ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

( rac )-5-Chloro- N- (1-ethyl-3-piperidinyl)oxazolo[4,5- b ]pyridin-2-amine ( Example 1 , Step 1) (92 mg , 0.311 mmol, 1.0 eq), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-( Trifluoromethyl)phenol (CAS # 2557358-38-8, 136 mg, 0.450 mmol, 1.45 eq), XPhos Pd G3 (27 mg, 0.032 mmol, 0.102 eq) and cesium carbonate (305 mg, 0.936 mmol, 3.01 eq ) in 1,4-dioxane (1.2 mL) and water (0.30 mL) was flushed with argon and stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was absorbed on ISOLUTE HM-N and analyzed by flash chromatography (silica gel, 12 g, gradient: 0% to 100% in dichloromethane (dichloromethane:methanol:NH ₄ OH 9:1: 0.05)) Purified. All fractions containing product were combined to give the title compound (82 mg, 60% yield) as a light yellow solid. LCMS: m / z 421.3 [M+H]+, ESI pos. Examples 2 , 2A and 2B : ( racemic )-2-[2-[3-[( dimethylamino ) methyl ] morpholin- 4- yl ] oxazolo [4,5- b ] pyridine -5- yl ]-3- methyl -5-( trifluoromethyl ) phenol and corresponding enantiomers 2A and 2B

step 1 : ( Racemization )-1-[4-(5- Chlorazolo [4,5- b ] pyridine -2- base ) Morpholine -3- base ]-N ,N- Dimethyl - Methylamine

To 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 80 mg, 0.379 mmol, 1.0 eq) in ( racemic )- N - Dimethyl(morpholin-3-ylmethyl)amine (CAS # 128454-20-6, 61 mg, 0.423 mmol, 1.12 eq) was added to the mixture in methyl-2-pyrrolidone (0.720 mL), Then triethylamine (0.060 mL, 0.430 mmol, 1.14 eq) was added. The brown solution was stirred at 150°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed four times with water and once with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 12 g, gradient: 0% to 5% methanol in dichloromethane) to afford the title compound (85 mg, 72% yield) as a light brown oil. LCMS: m / z 297.2 [M+H]+, ESI pos.

step 2 : ( Racemization )-2-[2-[3-[( Dimethylamino ) methyl ] Morpholine -4- base ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

( racemic )-1-[4-(5-chlorozozolo[4,5- b ]pyridin-2-yl)morpholin-3-yl]-N ,N -dimethyl-methylamine ( Example 2 , step 1) (79 mg, 0.253 mmol, 1 eq), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol Alk-2-yl)-5-(trifluoromethyl)phenol (CAS # 2557358-38-8, 111 mg, 0.367 mmol, 1.45 eq), cesium carbonate (237 mg, 0.727 mmol, 2.88 eq) and XPhos Pd A mixture of G3 (21 mg, 0.025 mmol, 0.098 eq) in 1,4-dioxane (1.0 mL) and water (0.250 mL) was flushed with argon and stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 5% methanol in dichloromethane). All fractions containing product were combined to give the title compound (93 mg, 80% yield) as a pale yellow foam. LCMS: m / z 437.4 [M+H] ⁺ , ESI pos.

step 3 : 2-[2-[(3 R or 3 S )-3-[( Dimethylamino ) methyl ] Morpholine -4- base ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) Phenol and 2-[2-[(3 S or 3 R )-3-[( Dimethylamino ) methyl ] Morpholine -4- base ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

The racemate ( rac )-2-[2-[3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5- b ]pyridine-5 -yl]-3-methyl-5-(trifluoromethyl)phenol ( Example 2 , step 2 ) (60 mg, 0.131 mmol, 1 eq) by chiral SFC (column: Chiralpak IC, eluent B: 15% Methanol + 0.2% Diethylamine) Purification to give two enantiomers: Example 2A as light brown foam (eluted first, retention time = 1.51 min) (23 mg, 38% yield); m / z 437.3 [M+H]+, ESI pos; and Example 2B as light brown foam (2nd eluate, retention time = 1.74 min) (27 mg, 45% yield). LCMS: m / z 437.3 [M+H]+, ESI pos. Examples 3 , 3A and 3B : ( racemic )-1-[5-[2- hydroxy -6- methyl -4-( trifluoromethyl ) phenyl ] oxazolo [4,5- b ] pyridine -2- yl ] piperidin -3- ol and the corresponding enantiomers 3A and 3B

step 1 : ( Racemization )-1-(5- Chlorazolo [4,5- b ] pyridine -2- base ) piperidine -3- alcohol

5-Chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 100 mg, 0.473 mmol, 1.0 eq), piperidin-3-ol (CAS #6859-99-0, 53 mg, 0.524 mmol, 1.11 eq) and triethylamine (0.073 mL, 0.524 mmol, 1.1 eq) in 1,4-dioxane (1.0 mL) were stirred at 90°C for 16 Hour. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated aqueous NaHCO ₃ . The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 70% ethyl acetate in heptane) to give the title compound (117 mg, yield 93%). LCMS: m / z 254.1 [M+H] ⁺ , ESI pos.

step 2 : ( Racemization )-1-[5-[2- Methoxy -6- methyl -4-( Trifluoromethyl ) Phenyl ] zozolo [4,5- b ] pyridine -2- base ] piperidine -3- alcohol

( rac )-1-(5-Chloroxazolo[4,5- b ]pyridin-2-yl)piperidin-3-ol ( Example 3 , Step 1) (117 mg, 0.438 mmol, 1.0 eq), 2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborane (CAS # 2557358-25-3, 194 mg, 0.614 mmol, 1.4 eq), potassium carbonate (305 mg, 2.21 mmol, 5.04 eq) and 1,1'-bis(diphenylphosphino)bis A mixture of ferrocene-palladium(ii) dichloromethane complex (44 mg, 0.054 mmol, 0.123 eq) in 1,4-dioxane (2.8 mL) and water (1.4 mL) was flushed with argon , and stirred at 110°C for 4 hours, and at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up in ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 5% methanol in dichloromethane) to give the title compound as a light brown waxy solid ( 194 mg, yield 98%, purity 90%). LCMS: m / z 408.3 [M+H]+, ESI pos.

step 3 : ( Racemization )-1-[5-[2- hydroxyl -6- methyl -4-( Trifluoromethyl ) Phenyl ] zozolo [4,5- b ] pyridine -2- base ] piperidine -3- alcohol

( racemic )-1-[5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5- b ]pyridine- 2-yl]piperidin-3-ol ( Example 3 , Step 2) (194 mg, 0.429 mmol, 1.0 eq, 90% purity) To a solution in dichloromethane (0.800 mL) was added boron tribromide dropwise (1 M solution in dichloromethane) (3.98 g, 1.5 mL, 1.5 mmol, 3.5 eq). Stir at 0°C for 15 minutes and at room temperature for 3 hours. The reaction mixture was cooled to 0 °C, and methanol (about 3 mL) was added dropwise. Stir at 0°C for about 15 minutes. Then, the mixture was added to saturated aqueous NaHCO ₃ and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 5% methanol in dichloromethane) to give the title compound 3 (134 mg, yield 76%). LCMS: m / z 394.3 [M+H]+, ESI pos.

step 4 : ( 3R or 3S )-1-[5-[2- hydroxyl -6- methyl -4-( Trifluoromethyl ) Phenyl ] zozolo [4,5- b ] pyridine -2- base ] piperidine -3- Alcohol and ( 3S or 3R )-1-[5-[2- hydroxyl -6- methyl -4-( Trifluoromethyl ) Phenyl ] zozolo [4,5-b] pyridine -2- base ] piperidine -3- alcohol

The racemate ( rac )-1-[5-[2-hydroxyl-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5- b ]pyridine-2 -yl]piperidin-3-ol ( example 3 , step 3) (100 mg, 0.254 mmol) by chiral SFC (column: OJ-H, 5 µm, 250 × 20 mm; eluent B: 15 % methanol) to give two enantiomers after trituration with a mixture of ethyl acetate/heptane = 1:1: Example 3A as a white solid (eluted first, retention time = 3.65 min) (44 mg, Yield 42%), m / z 394.3 [M+H]+, ESI pos; and Example 3B as an off-white solid (2nd elution, retention time=3.96 minutes) (23 mg, 21% yield, purity 90 %). LCMS: m / z 394.3 [M+H] ⁺ , ESI pos. Example 4 : 3- Methyl -2-(2- morpholinozozolo [4,5- b ] pyridin -5- yl )-5-( trifluoromethyl ) phenol

step 1 : 5- chlorine -2- Morpholinyl - zozolo [4,5- b ] pyridine

To 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS # 1783370-92-2, 100 mg, 0.473 mmol, 1.0 eq) in 1,4-dioxane ( To the mixture in 1.0 mL) was added morpholine (CAS # 110-91-8, 0.046 mL, 0.528 mmol, 1.12 eq) followed by triethylamine (0.074 mL, 0.531 mmol, 1.12 eq). The brown solution was stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated aqueous NaHCO ₃ . The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 80% ethyl acetate in heptane) to afford the title compound (97 mg, yield 81%). LCMS: m / z 240.1 [M+H] ⁺ , ESI pos.

step 2 : 5-[2- Methoxy -6- methyl -4-( Trifluoromethyl ) Phenyl ]-2- Morpholinyl - zozolo [4,5- b ] pyridine

5-Chloro-2-morpholino-oxazolo[4,5- b ]pyridine ( Example 4 , step 1) (94 mg, 0.373 mmol, 1.0 eq), 2-[2-methoxy-6 -Methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS # 2557358-25-3, 165 mg, 0.522 mmol, 1.4 eq), potassium carbonate (260 mg, 1.88 mmol, 5.05 eq) and 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride(ii) dichloromethane A mixture of the complex (37 mg, 0.045 mmol, 0.122 eq) in 1,4-dioxane (2.4 mL) and water (1.2 mL) was flushed with argon and stirred at 110°C for 3 hours, then at room temperature Stir for 16 hours. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 70% ethyl acetate in heptane) to give the title compound ( 112 mg, yield 65%, purity 85%). LCMS: m / z 394.3 [M+H]+, ESI pos.

step 3 : 3- methyl -2-(2- Morpholinozozolo [4,5- b ] pyridine -5- base )-5-( Trifluoromethyl ) phenol

To 5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-2-morpholinyl-oxazolo[4,5- b ]pyridine ( example 4 , step 2) (112 mg, 0.242 mmol, 1.0 eq, 85% purity) to a solution in dichloromethane (0.460 mL) was added dropwise boron tribromide (1 M solution in dichloromethane) (2.28 g , 0.860 mL, 0.860 mmol, 3.55 eq). Stir at 0°C for 15 minutes and at room temperature for 3 hours. The reaction mixture was cooled to 0 °C, and methanol (about 3 mL) was added dropwise. Stir at 0°C for about 15 minutes. Then, the mixture was added to saturated aqueous NaHCO ₃ and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 50% ethyl acetate in heptane) to afford the title compound (48 mg, yield 50%). LCMS: m / z 380.2 [M+H]+, ESI pos. Example 5 : ( racemic )-[2-[2-( hydroxymethyl ) morpholin -4- yl ] oxazolo [4,5- b ] pyridin -5- yl ]-3- methyl -5 -( trifluoromethyl ) phenol

step 1 : ( Racemization )-[4-(5- Chlorazolo [4,5- b ] pyridine -2- base ) Morpholine -2- base ] Methanol

To 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 80 mg, 0.379 mmol, 1.0 eq) in 1,4-dioxane ( 0.80 mL) was added ( racemic )-morpholin-2-ylmethanol (CAS # 103003-01-6, 50 mg, 0.427 mmol, 1.13 eq) followed by triethylamine (0.060 mL, 0.430 mmol, 1.14 eq). The brown solution was stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated aqueous NaHCO ₃ . The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 100% ethyl acetate in heptane) to give the title compound (90 mg, yield 84%). LCMS: m / z 270.1 [M+H]+, ESI pos.

step 2 : ( Racemization )-[2-[2-( Hydroxymethyl ) Morpholine -4- base ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

( rac )-[4-(5-Chloroxazolo[4,5- b ]pyridin-2-yl)morpholin-2-yl]methanol ( Example 5 , Step 1) (87 mg, 0.306 mmol, 1 eq), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoro Methyl)phenol (CAS # 2557358-38-8, 134 mg, 0.444 mmol, 1.45 eq), XPhos Pd G3 (26 mg, 0.031 mmol, 0.100 eq) and cesium carbonate (300 mg, 0.921 mmol, 3.0 eq) in A mixture of 1,4-dioxane (1.2 mL) and water (0.30 mL) was flushed with argon and stirred at 100°C for 2 hours and at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 5% methanol in dichloromethane). All fractions containing product were combined and concentrated in vacuo. The residue was absorbed on ISOLUTE HM-N and analyzed by flash chromatography (silica gel, 12 g, gradient: 0% to 50% in dichloromethane (dichloromethane:methanol:NH ₄ OH 9:1: 0.05)) to afford the title compound (99 mg, 75% yield) as an off-white foam. LCMS: m / z 410.3 [M+H]+, ESI pos. Example 6 : 3- methyl -2-(2- piperazin- 1- yloxazolo [4,5- b ] pyridin -5- yl )-5-( trifluoromethyl ) phenol formate

step 1 : 5-[2- Methoxy -6- methyl -4-( Trifluoromethyl ) Phenyl ]-2- Piperazine -1- base - zozolo [4,5- b ] pyridine

5-Chloro-2-piperazin-1-yl-oxazolo[4,5-b]pyridine (CAS #2504954-78-1, WO2020207941A1) (119.4 mg, 0.500 mmol, 1 eq), 2-[ 2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS # 2557358-25-3, 268 mg, 0.848 mmol, 1.7 eq), potassium carbonate (330 mg, 2.39 mmol, 4.78 eq) and 1,1'-bis(diphenylphosphino)ferrocene-dichloride A mixture of palladium(ii) dichloromethane complex (42.7 mg, 0.058 mmol, 0.116 eq) in 1,4-dioxane (3 mL) and water (1.5 mL) was flushed with argon and stirred at 110°C 5 hours. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product (dark brown solid, 304.5 mg) was absorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 15% MeOH in dichloromethane) to give The title compound (158.1 mg, 77% yield) as a brown solid. LCMS: m/z 393.3 [M+H]+, ESI pos.

step 2 : 3- methyl -2-(2- Piperazine -1- Subazolo [4,5- b ] pyridine -5- base )-5-( Trifluoromethyl ) Phenol; Formate

Add to the above 5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-2-piperazin-1-yl-㗁 at -75°C (bath containing dry ice and acetone) To a solution of azolo[4,5- b ]pyridine ( Example 6 , Step 1) (123.1 mg, 0.314 mmol, 1.0 eq, 95% purity) in dichloromethane (1.6 mL) was added boron tribromide dropwise (1 M solution in dichloromethane) (1.1 mL, 1.10 mmol, 3.5 eq). Stir at this temperature for 1 hour, then allow to warm to room temperature overnight. The reaction mixture was cooled to -75 °C, and methanol (about 20 mL) was added dropwise. The red solution was stirred for about 5 minutes. Then, the mixture was added to saturated aqueous NaHCO ₃ (until the pH was adjusted to 7) and extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (column: YMC-Triart C ₁₈ , 12 nm, 5 µm, 100 x 30 mm; eluent: acetonitrile/water+0.1% HCOOH) to give the title compound as a colorless solid , which was the formate salt (50.6 mg, 50% yield, 93% purity). LCMS: m / z 377.3 [M+H]+, ESI pos. Example 7 : 3- methyl -2-[2-[[3-( methylamino ) cyclohexyl ] amino ] oxazolo [4,5- b ] pyridin -5- yl ]-5-( tri Fluoromethyl ) phenol

step 1 : N -[3-[(5- Chlorazolo [4,5- b ] pyridine -2- base ) Amino ] Cyclohexyl ] -N- methyl - Tertiary butyl carbamate

To 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS # 1783370-92-2, 88 mg, 0.439 mmol, 1.0 eq) in 1,4-dioxane ( 0.90 mL) was added N- (3-aminocyclohexyl) -N -methyl-carbamic acid tertiary butyl ester (CAS # 1783996-31-5, 100 mg, 0.438 mmol, 0.99 eq), then Add triethylamine (67.3 µL, 0.438 mmol, 1.1 eq). The clear yellow solution was stirred at 90°C for 24 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 12 g, gradient: 0% to 10% methanol in dichloromethane) to afford the title compound (115 mg, yield 55%, purity 80 %). LCMS: m/z 381.3 [M+H] ⁺ , ESI pos.

step 2 : N -[3-[[5-[2- Methoxy -6- methyl -4-( Trifluoromethyl ) Phenyl ] zozolo [4,5- b ] pyridine -2- base ] Amino ] Cyclohexyl ] -N- methyl - Tertiary butyl carbamate

To the above N- [3-[(5-chloroazolo[4,5-b]pyridin-2-yl)amino]cyclohexyl]-N-methyl-carbamic acid tertiary butyl ester (example 7, Step 1) (115 mg, 0.242 mmol, 1 eq), 2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl 1,3,2-dioxaborolane (CAS # 2557358-25-3, 129.8 mg, 0.411 mmol, 1.7 eq), potassium carbonate (159.5 mg, 1.15 mmol, 4.78 eq) and 1,1 '-Bis(diphenylphosphino)ferrocene-dichloropalladium(ii) dichloromethane complex (22.8 mg, 0.028 mmol, 0.116 eq) in 1,4-dioxane (1.4 mL) and water (0.7 mL) was flushed with argon and stirred at 110°C for 24 hours (to complete the reaction, 0.5 eq of catalyst and base were added; again, the reaction mixture was stored in the refrigerator for 3 days before the reaction was complete). The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product (dark brown oil) was absorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 15% MeOH in dichloromethane) to give green The title compound as a solid (78.9 mg, 52% yield, 85% purity). LCMS: m/z 535.5 [M+H]+, ESI pos.

step 3 : 3- methyl -2-[2-[[3-( Methylamino ) Cyclohexyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-5-( Trifluoromethyl ) phenol

To the above N- [3-[[5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4 ,5- b ]pyridin-2-yl]amino]cyclohexyl] -N -methyl-carbamic acid tert -butyl ester ( Example 7 , step 2) (78.9 mg, 0.148 mmol, 1.0 eq) in dichloromethane To the solution in (2 mL) was added boron tribromide (1 M solution in dichloromethane) (664.2 µL, 0.664 mmol, 4.5 eq) dropwise. Stir at this temperature for 1 hour, then allow to warm to room temperature over a day. The reaction mixture was cooled to 0 °C and a few drops of methanol were added. The clear yellow solution was stirred for about 5 minutes. Then, the mixture was added to saturated aqueous NaHCO ₃ (until the pH was basic) and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was subjected to reverse phase HPLC (column: YMC-Triart C ₁₈ , 12 nm, 5 µm, 100 × 30 mm; eluent: acetonitrile/water+0.1% triethylamine) to obtain the title as off-white solid Compound, which is most likely a cis/trans diastereomeric mixture = 2:1 (30 mg, 30% yield, 85% purity). LCMS: m / z 421.1853 [M+H] ⁺ , ESI pos. Example 8 : 3- methyl -2-(2- piperazin- 1- yl - 1H - imidazo [4,5- b ] pyridin -5- yl )-5-( trifluoromethyl ) phenol; 2 ,2,2- Trifluoroacetic acid

step 1 : 5- bromine -1 H - imidazo [4,5- b ] pyridine -2- alcohol

To a mixture of 6-bromopyridine-2,3-diamine (1.0 g, 5.32 mmol, 1 eq) in 1,4-dioxane (30 mL) was added carbonyldiimidazole at 25 °C under _N2 (974.36 mg, 6.91 mmol, 1.3 eq). The mixture was then heated and stirred at 90°C for 4 hours. The mixture was concentrated in vacuo. The crude product was triturated with MTBE (10 mL x 3). The solid was collected to give the title compound (770 mg, 68% yield) as a black solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.57 (br. s, 1H), 11.01 (s, 1H), 7.18 (d, 1H), 7.12 (d, 1H).

step 2 : 5- bromine -2- chlorine -1 H - imidazo [4,5- b ] pyridine

The above 5-bromo-1 H -imidazo[4,5- b ]pyridin-2-ol ( Example 8 , step 1) (300.0 mg, 1.4 mmol, 1 eq) and POCl ₃ (4298.3 mg, 28.03 mmol, A mixture of 20 eq) in toluene (2 mL) was stirred at 110°C for 5 hours. The mixture was concentrated under reduced pressure to give the title compound (400 mg, 18% yield, HCl salt) as a brown solid. LCMS: m/z 233.8 [M+H]+, ESI pos.

step 3 : 4-(5- bromine -1 H - imidazo [4,5- b ] pyridine -2- base ) Piperazine -1- Tertiary butyl formate

To the _above 5-bromo-2-chloro- 1H -imidazo[4,5- b ]pyridine; hydrochloride ( Example 8 , step 2) (400.0 mg, 0.250 mmol, 1.0 eq), piperazine-1-carboxylic acid tertiary butyl ester (231.59 mg, 1.24 mmol, 5 eq) in the mixture in N -methylpyrrolidone (10 mL) was added K ₂ CO ₃ (274.6 mg, 1.99 mmol, 8.0 eq). The mixture was then stirred at 90°C for 4 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase flash chromatography (0.1% TFA conditions) to afford the title compound (40 mg, 38% yield) as a brown solid. LCMS: m/z 384.0 [M+2H] ⁺ , ESI pos.

step 4 : 4-(5-(2- hydroxyl -6- methyl -4-( Trifluoromethyl ) Phenyl )-1 H- imidazo [4,5- b ] pyridine -2- base ) Piperazine -1- Tertiary butyl formate

To the _above tertiary butyl 4-(5-bromo- 1H -imidazo[4,5- b ]pyridin-2-yl)piperazine-1- carboxylate ( Example 8 , step 3) (40.0 mg, 0.100 mmol, 1.0 eq), (2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boronic acid (34.5 mg, 0.160 mmol, 1.5 eq), Na ₂ CO ₃ (33.3 mg, 0.310 mmol, 3 eq) To a mixture in 1,4-dioxane (2 mL)/water (1 mL) was added Pd(dppf)Cl ₂ (7.66 mg, 0.010 mmol, 0.100 eq). The mixture was then stirred at 95°C for 2 hours. The mixture was poured into water (10 mL), and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column using petroleum ether/ethyl acetate=1/1 to obtain the title compound (20 mg, yield 33%) as light yellow solid. LCMS: m/z 478.0 [M+H]+, ESI pos.

step 5 : 3- methyl -2-(2- Piperazine -1- base -1 H - imidazo [4,5- b ] pyridine -5- base )-5 ( Trifluoromethyl ) phenol; 2,2,2- Trifluoroacetate

The above 4-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-1 H -imidazo[4,5- b ]pyridin-2-yl)piperazine- A mixture of tert- butyl 1-carboxylate ( Example 8 , step 4) (20.0 mg, 0.030 mmol, 1 eq), TFA (94.2 mg, 1.02 mmol, 30 eq) in dichloromethane (1 mL) was added at 25 °C Stir for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C ₁₈ 75 x 30 mm x 3 um, water (TFA)-acetonitrile, 12% to 42%, 7 min) to give the title compound as a pale yellow solid (4.69 mg, 27% yield). m/z 378.0 [M+H]+, ESI pos. Example 9 : ( racemic ) -5-(5-(2- hydroxyl -6- methyl -4-( trifluoromethyl ) phenyl ) oxazolo [4,5- b ] pyridin -2- yl ) piperidin -2- one

step 1 : ( Racemization ) -5-(5- bromozolo [4,5- b ] pyridine -2- base ) piperidine -2- ketone

2-Amino-6-bromopyridin-3-ol (CAS # 934758-27-7, 150.0 mg, 0.790 mmol, 1.0 eq) and ( racemic )-6-oxopiperidine-3-carboxylic acid ( A solution of CAS # 22540-50-7, 113.6 mg, 0.790 mmol, 1.0 eq) in polyphosphoric acid (1.0 mL) was stirred at 135°C for 12 hours. The above reaction mixture was diluted with cold water (50 mL) and treated with saturated sodium carbonate to adjust the pH to about 10, then extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (0.1% TFA conditions) to afford the title compound (50 mg, 11% yield) as a yellow solid. LCMS: m/z 296.0 [M+2H] ⁺ , ESI pos.

step 2 : ( Racemization )- 5-(5-(2- hydroxyl -6- methyl -4-( Trifluoromethyl ) Phenyl ) zozolo [4,5- b ] pyridine -2- base ) piperidine -2- ketone

To ( rac )-5-(5-bromooxazolo[4,5- b ]pyridin-2-yl)piperidin-2-one ( Example 9 , Step 1 ) (40.0 mg, 0.140 mmol, 1.0 eq) To a solution of 1,4-dioxane (2 mL) and water (0.40 mL) was added (2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boronic acid (59.4 mg , 0.270 mmol, 2.0 eq), Na ₂ CO ₃ (42.9 mg, 0.410 mmol, 3.0 eq) and Pd(dppf)Cl ₂ (19.8 mg, 0.030 mmol, 0.20 eq). The above reaction mixture was stirred at 100 °C for 2 h under _N2 gas. The above reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 µm; conditions: water (ammonium hydroxide v/v) - acetonitrile; B 18 at the beginning and B 48 at the end; gradient time (min ): 9; 100% B hold time (min): 2; flow rate (mL/min): 25) to give the title compound (2.04 mg, 4% yield) as a white solid. LCMS: m/z 392.0 [M+H] ⁺ ESI pos. Example 10 : ( racemic ) -3- methyl -2-[2-[3-( methylamino )-1- piperidinyl ] oxazolo [4,5- b ] pyridin -5- yl ]-5-( trifluoromethyl ) phenol

step 1 : N -[1-(5- Chlorazolo [4,5- b ] pyridine -2- base )-3- piperidinyl ] -N- methyl - Carbamic acid ( Racemization )- Level three Butyl ester

To 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 90 mg, 0.449 mmol, 1 eq) in 1,4-dioxane ( 0.90 mL) was added ( racemic ) -N -methyl- N- (3-piperidinyl)carbamate tertiary butyl ester (CAS # 172478-01-2, 95 µL, 0.449 mmol, 1 eq), then triethylamine (69 µL, 0.493 mmol, 1.1 eq) was added. The clear brown solution was stirred at 90°C for two days. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 12 g, gradient: 0% to 5% methanol in dichloromethane) to afford the title compound (139.2 mg, 81% yield) as an off-white solid. LCMS: m/z 367.3 [M+H] ⁺ , ESI pos.

step 2 : N -[1-[5-[2- Methoxy -6- methyl -4-( Trifluoromethyl ) Phenyl ] zozolo [4,5- b ] pyridine -2- base ]-3- piperidinyl ] -N- methyl - Carbamic acid ( Racemization )- Level three Butyl ester

Under N ₂ , at 25°C, to the above N-[1-(5-chloroazolo[4,5-b]pyridin-2-yl)-3-piperidinyl]-N-methyl-carbamic acid ( rac ) -tertiary butyl ester ( Example 10 , Step 10) (139.2 mg, 0.379 mmol, 1.0 eq), 2-[2-methoxy-6-methyl-4-(trifluoromethyl) Phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (179.9 mg, 0.569 mmol, 1.5 eq), Na ₂ CO ₃ (250.7 mg, 1.81 mmol , 4.78 eq) To a mixture in 1,4-dioxane (2.3 mL)/water (1.1 mL) was added Pd(dppf)Cl ₂ (35.9 mg, 0.044 mmol, 0.116 eq). The mixture was then stirred at 110°C for 2 days. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 12 g, gradient: 0% to 10% methanol in dichloromethane) to afford the title compound (122.8 mg, 48% yield, 77% purity) as a dark brown solid. %). LCMS: m/z 521.5 [M+H] ⁺ ESI pos.

step 3 : ( Racemization )- 3- methyl -2-[2-[3-( Methylamino )-1- piperidinyl ] zozolo [4,5- b ] pyridine -5- base ]-5-( Trifluoromethyl ) phenol

The above ( racemic ) -tertiary butane N- [1-[5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5- b ] pyridin-2-yl]-3-piperidinyl]-N-methyl-carbamic acid tertiary butyl ester ( Example 10 , step 2 ) (78.9 mg, 0.152 mmol, 1.0 eq), 3-methyl- 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS # 2557358-38- 8, 682 µL, 0.682 mmol, 4.5 eq), XPhos Pd G3 (11.3 mg, 0.013 mmol, 0.098 eq) and cesium carbonate (12.2 mg, 0.373 mmol, 2.88 eq) in 1,4-dioxane (0.5 mL) and water (0.2 mL) was flushed with argon and stirred at 100°C for 5 hours. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product (yellow oil, 114 mg) was purified by HPLC (column: Phenomenex Gemini NX C ¹⁸ - 5 µm- 110 Å - 100 × 30 mm; mobile phase H ₂ O+0.1% triethylamine/acetonitrile ( Gradient) over 15 min to afford the title compound (32.4 mg, 53% yield, 90% purity) as an off-white solid. LCMS: m/z 419.5 [MH] ^- , ESI neg. Example 11 : ( racemic )-3- methyl -2-[2-( tetrahydropyran -3- ylamino ) oxazolo [4,5- b ] pyridin -5- yl ]-5- ( Trifluoromethyl ) phenol

step 1 : ( Racemization )-5- chlorine - N - Tetrahydropyran -3- base - zozolo [4,5- b ] pyridine -2- amine

To 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 100 mg, 0.498 mmol, 1 eq) in 1,4-dioxane ( 2.8 mL) was added ( racemic )-tetrahydropyran-3-ylamine (55.5 mg, 57.6 µL, 0.548 mmol, 1.1 eq) followed by triethylamine (56.5 mg, 77.8 µL, 0.558 mmol, 1.12 eq). The brown solution was stirred overnight at 90 °C. The reaction mixture was cooled to room temperature and extracted with about 40 mL of ethyl acetate and about 5 mL of saturated NaHCO ₃ solution. The aqueous layer was back extracted with about 40 mL of ethyl acetate. The organic layer was washed with about 5 mL of water and about 5 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 4 g, gradient: 0% to 10% methanol in dichloromethane) to afford the title compound (63 mg, 59%) as a white solid. LCMS: m/z = 254.1 [M+H] ⁺ , ESI pos.

step 2 : ( Racemization )-3- methyl -2-[2-( Tetrahydropyran -3- Amino ) zozolo [4,5- b ] pyridine -5- base ]-5-( Trifluoromethyl ) phenol

Under argon, the above ( racemic )-(5-chloroazolo[4,5- b ]pyridin-2-yl)-tetrahydropyran-3-yl-amine ( Example 11 , step 1 ) (50 mg, 0.197 mmol, 1.0 eq) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5-(Trifluoromethyl)phenol (CAS # 2557358-38-8, 86.5 mg, 71.5 µL, 0.286 mmol, 1.45 eq) in extra dry 1,4-dioxane (0.8 mL) and water (0.2 mL ) was added cesium carbonate (184.7 mg, 0.567 mmol, 2.88 eq) followed by XPhos Pd G3 (17.2 mg, 0.019 mmol, 0.098 eq). The reaction mixture was flushed with argon and stirred at 100 °C for one hour. After the reaction was complete, the mixture was cooled to room temperature, and extracted with about 5 mL of ethyl acetate and about 5 mL of water. The aqueous layer was back extracted with about 5 mL of ethyl acetate. The organic layer was washed with about 5 mL of water and about 5 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 4 g, gradient: 0% to 10% methanol in dichloromethane). All fractions containing product were combined to give the title compound (44 mg, 57%) as a white solid. LCMS: m/z 394.3 [M+H] ⁺ , ESI pos. Example 12 : 1-[5-[2- Hydroxy - 6- methyl -4-( trifluoromethyl ) phenyl ] oxazolo [4,5-b] pyridin -2- yl ] tetrahydroazine- 3- ol

step 1 : 1-(5- Chlorazolo [4,5- b ] pyridine -2- base ) Tetrahydroacridine -3- alcohol

To 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 0.100 g, 0.473 mmol, 1.0 eq) in 1,4-dioxane ( 1 mL) was added tetrahydroazin-3-ol (CAS # 45347-82-838.3 mg, 0.524 mmol, 1.11 eq) followed by triethylamine (53.7 mg, 74 µL, 0.531 mmol, 1.12 eq ). The brown solution was stirred overnight at 90 °C. The reaction mixture was cooled to room temperature and extracted with about 20 mL of ethyl acetate, 20 mL of dichloromethane (solubility issue) and about 5 mL of saturated NaHCO ₃ solution. The aqueous layer was back extracted with about 40 mL of dichloromethane. The organic layer was washed with about 5 mL of water and about 5 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 4 g, gradient: 0% to 10% methanol in dichloromethane) to afford the title compound (63 mg, 59%) as a white solid. LCMS: m/z = 226.1 [M+H] ⁺ , ESI pos.

step 2 : 1-[5-[2- hydroxyl -6- methyl -4-( Trifluoromethyl ) Phenyl ] zozolo [4,5- b ] pyridine -2- base ] Tetrahydroacridine -3- alcohol

Under argon, 1-(5-chloroazolo[4,5- b ]pyridin-2-yl)tetrahydroacri-3-ol (50 mg, 0.222 mmol, 1.0 eq) and 3-methanol yl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (97.3 mg, 80.4 µL, 0.322 mmol, 1.45 eq) To a solution of extra dry 1,4-dioxane (0.9 mL) in water (0.2 mL) was added cesium carbonate (207.7 mg, 0.637 mmol, 2.88 eq) followed by XPhos Pd G3 (19.4 mg, 0.022 mmol, 0.098 eq). The reaction mixture was flushed with argon and stirred at 100 °C for one hour. After the reaction was complete, the mixture was cooled to room temperature, and extracted with about 5 mL of ethyl acetate and about 5 mL of water. The aqueous layer was back extracted with about 5 mL of ethyl acetate. The organic layer was washed with about 5 mL of water and about 5 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 4 g, gradient: 0% to 10% methanol in dichloromethane). All fractions containing product were combined. The reaction mixture was purified by preparative HPLC. The title compound (10.3 mg, 12%) was obtained as a white solid after lyophilization. LCMS: m/z = 366.2 [M+H] ⁺ , ESI pos. Example 13 : 2-[2-[(3- hydroxycyclohexyl ) amino ] oxazolo [4,5- b ] pyridin -5- yl ]-3- methyl -5-( trifluoromethyl ) phenol

step 1 : 3-[(5- Chlorazolo [4,5- b ] pyridine -2- base ) Amino ] Cyclohexanol

To a solution of 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (0.080 g, 0.379 mmol, 1 eq) in 1,4-dioxane (0.8 mL) was added 3-Aminocyclohexanol (CAS # 6850-39-1, 48.2 mg, 0.419 mmol, 1.11 eq) followed by triethylamine (42.98 mg, 59.2 uL, 0.425 mmol, 1.12 eq) was added. The brown solution was stirred at 90°C for two days. LC-MS showed 43% starting material and 51% product. 3-Aminocyclohexanol (23.9 mg, 0.208 mmol, 0.550 eq) was added to the reaction mixture and stirred for five hours. LC-MS showed a small extractable peak. 3-Aminocyclohexanol (23.9 mg, 0.208 mmol, 0.550 eq) was added to the reaction mixture, and it was stirred at 90°C overnight. After the reaction was complete, the mixture was cooled to room temperature, and extracted with about 40 mL of ethyl acetate and about 5 mL of saturated NaHCO ₃ solution. The aqueous layer was back extracted with about 40 mL of ethyl acetate. The organic layer was washed with about 5 mL of water and about 5 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 4 g, gradient: 0% to 10% methanol in dichloromethane) to afford the title compound (79.6 mg, 79%) as a pale yellow solid. LCMS: m/z = 268.1 [M+H] ⁺ , ESI pos.

step 2 : 2-[2-[(3- Hydroxycyclohexyl ) Amino ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

To the above 3-[(5-chloroazolo[4,5- b ]pyridin-2-yl)amino]cyclohexanol ( Example 13 , Step 1 ) (75 mg, 0.280 mmol, 1.0 eq) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl ) phenol (122.9 mg, 101.6 µL, 0.407 mmol, 1.45 eq) To a solution of 1,4-dioxane (1 mL) and water (0.3 mL) was added cesium carbonate (262.5 mg, 0.806 mmol, 2.88 eq) , then XPhos Pd G3 (24.5 mg, 0.027 mmol, 0.098 eq) was added. The reaction mixture was flushed with argon and stirred at 100 °C for one hour. The reaction mixture was cooled to room temperature and extracted with about 5 mL of ethyl acetate and about 5 mL of water. The aqueous layer was back extracted with about 5 mL of ethyl acetate. The organic layer was washed with about 5 mL of water and about 5 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 4 g, gradient: 0% to 70% ethyl acetate in heptane) to give the title compound (80 mg , 67%). LCMS: m/z = 408.3 [M+H] ⁺ , ESI pos. Example 14 : 2-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridin -5- yl ]-3- methyl -5-( Trifluoromethyl ) phenol

step 1 : 5- chlorine - N -[(3 R )-1- Ethyl -3- piperidinyl ] zozolo [4,5- b ] pyridine -2- amine

To 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 320 mg, 1.52 mmol, 1 eq) in 1,4-dioxane ( 3.2 mL) was added (3 R )-1-ethylpiperidin-3-amine (CAS # 1020396-26-2, 240 mg, 1.76 mmol, 1.16 eq) followed by triethylamine (0.240 mL , 1.72 mmol, 1.14 eq). The brown solution was stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated aqueous NaHCO ₃ . The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient: 0% to 10% methanol in dichloromethane) to afford the title compound (405 mg , yield 90%). LCMS: m / z 281.2 [M+H] ⁺ , ESI pos.

step 2 : 2-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

5-Chloro- N -[( 3R )-1-ethyl-3-piperidinyl]oxazolo[4,5- b ]pyridin-2-amine ( Example 14 , Step 1) (300 mg, 1.02 mmol, 1 eq), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(tri Fluoromethyl)phenol (CAS # 2557358-38-8, 430 mg, 1.42 mmol, 1.4 eq), cesium carbonate (995 mg, 3.05 mmol, 3.01 eq) and XPhos Pd G3 (89 mg, 0.105 mmol, 0.10 eq) The mixture in 1,4-dioxane (4.0 mL) and water (1.0 mL) was flushed with argon and stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was absorbed on ISOLUTE HM-N and analyzed by flash chromatography (silica gel, 25 g, gradient: 0% to 100% in dichloromethane (dichloromethane:methanol:NH ₄ OH 9:1: 0.05)) Purified. All fractions containing product were combined and concentrated in vacuo. The residue was triturated with ethyl acetate/heptane to afford the title compound (328 mg, 73% yield) as an off-white solid. LCMS: m / z 421.3 [M+H] ⁺ , ESI pos. Example 15 : 3- methyl -2-[2-[[(3 R )-1- methyl -3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridin -5- yl ] -5-( Trifluoromethyl ) phenol

step 1 : 5- chlorine - N -[(3 R )-1- methyl -3- piperidinyl ] zozolo [4,5- b ] pyridine -2- amine

To 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS # 1783370-92-2, 80 mg, 0.379 mmol, 1 eq) in 1,4-dioxane ( 0.800 mL) was added (3 R )-1-methylpiperidin-3-amine (CAS # 1001353-92-9, 51 mg, 0.447 mmol, 1.18 eq), then triethylamine (0.061 mL , 0.438 mmol, 1.16 eq). The brown solution was stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated aqueous NaHCO ₃ . The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 10% methanol in dichloromethane) to afford the title compound (101 mg , yield 95%). LCMS: m / z 267.1 [M+H] ⁺ , ESI pos.

step 2 : 3- methyl -2-[2-[[(3 R )-1- methyl -3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-5-( Trifluoromethyl ) phenol

5-Chloro-N-[( 3R )-1-methyl-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine ( Example 15 , Step 1) (98 mg, 0.349 mmol, 1.0 eq), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(tri Fluoromethyl)phenol (CAS # 2557358-38-8, 140 mg, 0.463 mmol, 1.33 eq), cesium carbonate (325 mg, 0.997 mmol, 2.86 eq) and XPhos Pd G3 (29 mg, 0.034 mmol, 0.098 eq) The mixture in 1,4-dioxane (1.2 mL) and water (0.3 mL) was flushed with argon and stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were back extracted with a mixture of dichloromethane/methanol (9:1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was absorbed on ISOLUTE HM-N and analyzed by flash chromatography (silica gel, 12 g, gradient: 0% to 100% in dichloromethane (dichloromethane:methanol:NH ₄ OH 9:1: 0.05)) Purified. All fractions containing product were combined and concentrated in vacuo. The residue was triturated with ethyl acetate/heptane to afford the title compound (88 mg, 59%) as an off-white powder. LCMS: m / z 407.3 [M+H] ⁺ , ESI pos. Example 16 : ( racemic )-3- methyl -2-(2-(1- methylpiperidin -2- yl )-3H- imidazo [4,5- b ] pyridin -5- yl )- 5-( Trifluoromethyl ) phenol

step 1 : ( Racemization )- N -(2- Amino -6- Pyridine bromide -3- base )-1- Methylpiperidine -2- Formamide

( racemic )-1-methylpiperidine-2-carboxylic acid (456.88 mg, 3.19 mmol, 1 eq), 6-bromopyridine-2, 3-diamine (0.60 g, 3.2 mmol, 1.0 eq) and DIPEA (1.99 mL, 11.2 mmol, 3.5 eq) in DMF (10 mL) was added dropwise T ₃ P (3.05 g, 4.79 mmol, 1.5 eq in ethyl acetate, purity 50 %). The reaction mixture was stirred at 25 °C under nitrogen atmosphere for 2 hours. LCMS indicated starting material remained, so another batch of DIPEA (1.99 mL, 11.2 mmol, 3.5 eq) and _T3P (3045.92 mg, 4.79 mmol, 1.5 eq in ethyl acetate were added to the mixture at 25 °C 50% purity), and stirred at 50 °C for another 2 h under nitrogen atmosphere. The reaction mixture was quenched with water (30 mL), extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (CombiFlash 0.1% NH ₄ OH in water-acetonitrile conditions) and then lyophilized to give the title compound (400 mg, 35% yield) as a yellow solid. LCMS: m/z 313.0 [M+H] ⁺ , ESI pos.

step 2 : ( Racemization )-5- bromine -2-(1- Methylpiperidine -2- base )-3 H- imidazo [4,5- b ] pyridine

To the above ( racemic ) -N- (2-amino-6-bromopyridin-3-yl)-1-methylpiperidine-2-carboxamide ( Example 16 , Step 1 ) at 25°C (220 mg, 0.700 mmol, 1.0 eq) To a solution in ethanol (3 mL) and water (0.5 mL) was added NaOH (290.0 mg, 7.25 mmol, 10.3 eq). The reaction mixture was stirred at 100 °C for 20 h under nitrogen atmosphere. LCMS indicated starting material remained and another batch of NaOH (100 mg) was added. The reaction mixture was stirred for a further 18 hours at 100°C. The reaction mixture was diluted with 10 mL of water, and extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was analyzed by preparative HPLC (method: column Phenomenex luna C ₁₈ 150 × 40 mm × 15 μm; condition: water (0.1% TFA)-acetonitrile: B 23 at the beginning, B 53 at the end; gradient time (minutes ): 11; 100% B Retention time (min): 2; Flow rate (mL/min): 60) Purification and subsequent lyophilization gave the title compound (100 mg, 48% yield) as a yellow solid. ¹ H NMR (400 MHz, chloroform- d ) δ = 7.88 (d, 1H), 7.47 (d, 1H), 4.71 (d, 1H), 3.76 (d, 1H), 3.19 - 3.12 (m, 1H), 2.69 (s, 3H), 2.54 - 2.44 (m, 1H), 2.31 - 2.27 (m, 1H), 2.21 - 2.01 (m, 3H), 1.79 - 1.721 (m, 1H).

step 3 : ( Racemization )-5-(2- Methoxy -6- methyl -4-( Trifluoromethyl ) Phenyl )-2-(1- Methylpiperidine -2- base ) -3 H - imidazo [4,5- b ] pyridine

The above ( racemic )-2-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3, 2-Dioxaborolane ( Example 16 , step 2 ) (85.68 mg, 0.270 mmol, 1 eq), 5-bromo-2-(1-methylpiperidin-2-yl) -3H -imidazole And[4,5- b ]pyridine (80.0 mg, 0.270 mmol, 1 eq) and K ₂ CO ₃ (201.08 mg, 1.9 mmol, 7 eq) in 1,4-dioxane (4 mL) and water (0.800 mL) was degassed and flushed with N ₂ three times, then Pd(dppf)Cl ₂ (66.4 mg, 0.080 mmol, 0.300 eq) was added to the mixture. The mixture was stirred at 100°C for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was subjected to reverse phase flash chromatography (CombiFlash 0.1% TFA aqueous solution/acetonitrile condition) and preparative HPLC (column: 3_Phenomenex Luna C ₁₈ 75 × 30 mm × 3 um; condition: water (0.1% TFA)-acetonitrile ; B at the start: 36, B at the end: 56; Gradient time (min): 8; 100% B hold time (min): 2; Flow rate (mL/min): 25) was purified and then lyophilized to obtain The title compound as a black solid (30 mg, 27% yield). LCMS: m/z 405.1 [M+H] ⁺ , ESI pos.

step 4 : ( Racemization )-3- methyl -2-(2-(1- Methylpiperidine -2- base )-3 H- imidazo [4,5- b ] pyridine -5- base )-5-( Trifluoromethyl ) phenol

To the above ( racemic )-5-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-2-(1-methylpiperidine-2- BBr 3 ( 2.0 _ _ _{_} mL, 20.76 mmol, 419.7 eq). The reaction mixture was stirred at -60°C for 2.5 hours and at 25°C under nitrogen atmosphere for another 0.5 hours. LCMS indicated starting material remained, so another batch of _BBr3 (2.0 mL, 20.76 mmol, 419.7 eq) was added to the mixture. The reaction mixture was stirred for an additional 1 h at 25 °C under nitrogen atmosphere. The reaction mixture was quenched with cooled water (5 mL), adjusted to pH ~8 with aqueous ammonia, and then concentrated under reduced pressure. The residue was triturated twice with methanol (10 mL), and the filtrate was passed through CombiFlash 0.1% TFA-water solution/acetonitrile condition and preparative HPLC (column: 3_Phenomenex Luna C ₁₈ 75 × 30 mm × 3 µm; condition: water ( 0.1% TFA in water)-acetonitrile; start: B 21, end: B 51; gradient time (min): 7, 100% B hold time (min): 2; flow rate (mL/min): 25), and Subsequent lyophilization gave the title compound (5.89 mg, 30% yield) as a white solid. LCMS: m/z 391.1 [M+H] ⁺ , ESI pos. Example 17 : ( racemic )-3- methyl -2-(2-( pyrrolidin- 2- yl ) -1H - imidazo [4,5- b ] pyridin -5- yl )-5-( Trifluoro - methyl ) phenol

step 1 : 2-((2- Amino -6- Pyridine bromide -3- base ) carbamoyl ) Pyrrolidine -1- formic acid ( Racemization )- Level three Butyl ester

To a solution of (rac )-( tertiary -butoxycarbonyl)proline (1.0 g, 4.65 mmol, 1 eq) in DMF (10 mL) was added DIPEA (1.22 g, 9.29 mmol) at 0 °C , 2 eq) and 6-bromopyridine-2,3-diamine (874 mg, 4.65 mmol, 1.0 eq), then T3P (3.25 g, 5.11 mmol, 1.1 eq in ethyl acetate, purity 50%) was added . The mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched with ice water (20 mL), then extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (CombiFlash 0.1% NH ₃ ·H ₂ O in water-acetonitrile) and then lyophilized to afford the title compound (1.0 g, 56% yield) as a brown solid. LCMS: m/z 387.1 [M+2+H] ⁺ , ESI pos.

step 2 : 2-(5- bromine -1 H - imidazo [4,5- b ] pyridine -2- base ) Pyrrolidine -1- formic acid ( Racemization )- Level three Butyl ester

To ( racemic ) -tertiary butyl 2-((2-amino-6-bromopyridin-3-yl)carbamoyl)pyrrolidine-1-carboxylic acid tertiary butyl ester (500.0 mg, 1.3 mmol, To a solution of 1.0 eq) in ethanol (5 mL) was added a solution of NaOH (779 mg, 19.5 mmol, 15 eq) in water (1 mL). The reaction was stirred at 100°C for 4 hours. The reaction mixture was quenched with ice water (20 mL), extracted with ethyl acetate (20 mL × 3), washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed Concentrate. The residue was purified by reverse phase flash chromatography (CombiFlash 0.1% TFA in water-acetonitrile conditions) and then lyophilized to give the title compound (50 mg, 10% yield) as a pale yellow solid. LCMS: m/z 367.0 [M+H] ⁺ , ESI pos.

step 3 : 2-(5-(2- Methoxy -6- methyl -4-( Trifluoromethyl ) Phenyl )-1 H- imidazo [4,5- b ] pyridine -2- base ) Pyrrolidine -1- formic acid ( Racemization )- Level three Butyl ester

2-(5-Bromo-1 H -imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylic acid ( racemic ) -tertiary butyl ester; 2,2,2-tri Fluoroacetic acid (80.0 mg, 0.170 mmol, 1.0 eq), K ₂ CO ₃ (68.82 mg, 0.500 mmol, 3 eq) and 2-(2-methoxy-6-methyl-4-(trifluoromethyl) Phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (105.1 mg, 0.330 mmol, 2 eq) in 1,4-dioxane (2 mL ) and water (0.4 mL) was added to a round bottom flask and purged with nitrogen three times, then Pd(dppf)Cl ₂ (36.45 mg, 0.050 mmol, 0.300 eq) was added to the mixture. The reaction mixture was stirred at 90 °C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (PE:ethyl acetate=1:1, Rf=0.4) to obtain the title compound (79 mg, yield 99.7%) as a brown solid. LCMS: m/z 477.2 [M+H] ⁺ , ESI pos.

step 4 : ( Racemization )-3- methyl -2-(2-( Pyrrolidine -2- base )-1 H- imidazo [4,5- b ] pyridine -5- base )-5-( Trifluoromethyl ) phenol

Under N ₂ , to 2-(5-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-1 H -imidazo[4,5- b ]pyridine-2 -yl)pyrrolidine-1-carboxylic acid ( rac ) -tert-butyl ester (50.0 mg, 0.10 mmol, 1.0 eq) To a mixture in dichloromethane (1 mL) was added BBr ₃ (66.6 mg, 0.270 mmol , 2.53 eq). The mixture was stirred at 25°C for 10 minutes and then at 25°C for a further 50 minutes. The reaction mixture was quenched with ice water (2 mL) and neutralized to pH ~7 with NH ₃ ·H ₂ O. The residue was purified by reverse phase flash chromatography (CombiFlash 0.1% TFA in water-acetonitrile conditions) and then lyophilized to give the title compound (15.1 mg, 39% yield) as a white solid. LCMS: m/z 363.1 [M+H] ⁺ , ESI pos. Examples 18 , 18A and 18B : ( rac )-2-[2-[(1- ethyl -3- piperidinyl ) amino ] -1H - imidazo [4,5- b ] pyridine -5 -yl ]-3- methyl -5-( trifluoromethyl ) phenol and the corresponding enantiomers 18A and 18B

step 1 : 5- bromine -2- methylmercapto -1H- imidazo [4,5- b ] pyridine

To a solution of (2-amino-6-bromo-3-pyridyl)amine (CAS # 129012-04-0, 800 mg, 4.25 mmol, 1.0 eq) in DMF (40 mL) under argon gas 1,1'-thiocarbonyldiimidazole (CAS # 6160-65-2, 917.84 mg, 4.89 mmol, 1.15 eq) was added in portions. After the addition, the color of the yellow solution changed to black. The reaction mixture was stirred overnight at room temperature. LC-MS indicated detection of an intermediate, so potassium carbonate (1.18 g, 514 µL, 8.51 mmol, 2.0 eq) was added followed by methyl iodide (307.25 µL, 4.94 mmol, 1.16 eq). The reaction mixture was stirred at room temperature for 2 hours 30 minutes. After complete conversion (reaction control using TLC 1:1 ethyl acetate/hexane). The reaction mixture was cooled to 0 °C, and about 25 mL of water was added dropwise. The reaction mixture was diluted with additional water (25 mL) and extracted 3 times with ethyl acetate (20 mL). _The organic layer was washed with water and brine, dried over _Na2SO4 , and concentrated under reduced pressure. The residue was triturated with ether to give the title compound (618 mg, 60% yield) as a light brown powder. LCMS: m/z 244.0 [M+H] ⁺ (Br), ESI pos.

step 2 : ( Racemization )-(5- bromine - N -(1- Ethyl -3- piperidinyl )-1 H- imidazo [4,5- b ] pyridine -2- amine

In a sealed tube, add the above mixture of 5-bromo-2-methylsulfanyl- 1H -imidazo[4,5- b ]pyridine ( Example 18 , Step 1 ) (200 mg, 0.819 mmol, 1.0 eq ) was added ( racemic )-(1-ethyl-3-piperidinyl)amine (CAS # 6789-94-2, 552.9 mg, 615.7 µL, 4.1 mmol, 5.0 eq). The light yellow suspension was stirred at 150°C for 4 days and at 130°C for an additional day. After the reaction was complete, the reaction mixture was cooled to room temperature. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 15 g, gradient: 0% to 10% methanol in dichloromethane) to give the title compound (187 mg, 56%, purity 80%). LCMS: m/z 324.2 [M+H] ⁺ , ESI pos.

step 3 : ( Racemization )-2-[2-[(1- Ethyl -3- piperidinyl ) Amino ]-1 H- imidazo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

To the above ( racemic )-(5-bromo- 1H -imidazo[4,5- b ]pyridin-2-yl)-(1-ethyl-3-piperidinyl)amine ( Example 18 , step 2 ) (196.8 mg, 0.577 mmol, 1.0 eq) in 1,4-dioxane (3.3 mL) and water (1.65 mL) was added (2-hydroxy-6-methyl-4-(trifluoro Methyl)phenyl)boronic acid (314.8 mg, 1.43 mmol, 2.48 eq), potassium carbonate (559 mg, 4.04 mmol, 7.0 eq) and Pd(dppf)Cl ₂ (79.1 mg, 0.097 mmol, 0.17 eq). The reaction mixture was stirred at 85 °C for 6 hours under _N2 gas. The reaction mixture was cooled to room temperature and extracted with about 30 mL of ethyl acetate and about 4 mL of half-saturated NH ₄ Cl solution. The aqueous layer was back extracted with about 30 mL of ethyl acetate. The organic layer was washed with about 4 mL of water and about 4 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 10% methanol in dichloromethane) to give the title compound (110 mg, 46%). LCMS: m / z 418.4 [M+H] ⁺ , ESI pos.

step 4 : 2-[2-[[(3 R or 3 S )-1- Ethyl -3- piperidinyl ] Amino ]-1 H- imidazo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) Phenol and 2-[2-[[(3 S or 3 R )-1- Ethyl -3- piperidinyl ] Amino ]-1 H- imidazo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

The above ( Example 18 , Step 3 ) ( racemic )-2-[2-[(1-ethyl-3-piperidinyl)amino] -1H -imidazo[4,5- b ]pyridine -5-yl]-3-methyl-5-(trifluoromethyl)phenol by chiral SFC (column: chiral cellulose C4, 5 µm, 250 × 20 mm), eluent: methanol 35 % + 0.2% diethylamine) to give two enantiomers: Example 18A as a white powder (eluted first, retention time = 2.90 min, optical rotation (in MeOH, 20°C): +19.44°) (33.0 mg, yield 27%, purity 90%, containing diethylamine), m / z 418.4 [M+H] ⁺ , ESI pos; and white powdery Example 18B (second eluting, retention time=4.12 min) (28.0 mg, 25% yield). LCMS: m / z 418.4 [M+H] ⁺ , ESI pos. Example 19 : 5- chloro -2-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridin -5- yl ]- 3- Methyl - phenol

5-Chloro- N -[( 3R )-1-ethyl-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine ( Example 14 , Step 1 ) (450 mg, 1.52 mmol, 1.00 eq), (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (CAS # 1207961-50-9, 480 mg, 2.58 mmol, 1.69 eq), potassium carbonate (1.01 g, 7.31 mmol, 4.80 eq) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(ii) dichloromethane complex (189 mg, 0.23 mmol, 0.15 eq) at 1,4 - A mixture of dioxane (9.0 mL) and water (4.5 mL) was flushed with argon and stirred at 95°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and half-saturated aqueous _NH4Cl . The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 40 g, gradient: 0% to 10% methanol in dichloromethane). All fractions containing product were combined and concentrated in vacuo to give the title compound (414 mg, 67% yield) as a dark brown solid. LC-MS: m/z 387.2 [M+H] ⁺ , ESI pos. Examples 20 , 20A and 20B : ( rac )-5- chloro -3- methyl -2-[2-(6- methyl -3,3a,4,5,7,7a- hexahydro - 2H -pyrrolo [2,3- c ] pyridin -1- yl ) oxazolo [4,5- b ] pyridin -5- yl ] phenol and enantiomers 20A and 20B .

step 1 : ( Racemization )-5- chlorine -2-(6- methyl -3,3a,4,5,7,7a- Hexahydro -2H- pyrrolo [2,3- c ] pyridine -1- base ) zozolo [4,5- b ] pyridine

In a sealed tube, triethylamine (374 mg, 515 µL, 3.69 mmol, 3.0 eq) was added to 5-chloro-2-(methylthio)oxazolo[4,5- b with stirring at room temperature ]pyridine (CAS # 1783370-92-2, 260 mg, 1.23 mmol, 1.0 eq) and 6-methyloctahydro-1 H -pyrrolo[2,3- c ]pyridine (CAS # 1443980-22-0, 224 mg, 1.6 mmol, 1.3 eq) in a mixture of 1,4-dioxane (4 mL) and N -methyl-2-pyrrolidone (2 mL). The reaction mixture was heated at 120°C for 2 hours. Then, the dark brown reaction mixture was heated at 150 °C for 20 hours. The black reaction mixture was cooled to room temperature and extracted twice with ethyl acetate:tBME (v/v) 1:1 (2 × 50 mL). The organic layer was washed with water (20 mL) and brine (20 mL). The aqueous layer was back extracted with ethyl acetate:tBME (v/v) 1:1 (50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and flash-chromatographed (12 g SiO ₂ ; gradient: 0% to 10% methanol in dichloromethane) to give the title compound (313 mg, Yield 86%). LC-MS: m/z 293.1 [M+H] ⁺ , ESI pos.

step 2 : ( Racemization )-5- chlorine -3- methyl -2-[2-(6- methyl -3,3a,4,5,7,7a- Hexahydro -2H- pyrrolo [2,3- c ] pyridine -1- base ) zozolo [4,5- b ] pyridine -5- base ] phenol

5-Chloro-2-(6-methyl-3,3a,4,5,7,7a-hexahydro- 2H -pyrrolo[2,3- c ]pyridin-1-yl)oxazolo[ 4,5- b ]pyridine (112 mg, 0.379 mmol, 1.0 eq) and (4-chloro-2-hydroxyl-6-methyl-phenyl)boronic acid (141.2 mg, 0.757 mmol, 2.00 eq) were dissolved in 1, 4-Dioxane (3 mL) and water (1.5 mL). Potassium carbonate (235.6 mg, 1.7 mmol, 4.5 eq) was then added at room temperature. The orange reaction mixture was purged with argon, and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(ii) dichloromethane complex (61.9 mg, 0.076 mmol, 0.2 eq). The tube was sealed and stirred at 100°C for 20 hours. The reaction was then cooled to room temperature, and (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (70.6 mg, 0.379 mmol, 1.0 eq), then potassium carbonate (235.6 mg, 1.7 mmol, 4.5 eq) was added. The dark red reaction mixture was purged with argon, and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(ii)dichloromethane complex (30.9 mg , 0.038 mmol, 0.1 eq). The tube was sealed and stirring was continued at 110°C for 6 hours. Then, the reaction mixture was extracted twice with DCM (2 x 100 mL) and aqueous ammonium chloride (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL). The combined organic extracts were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (SiO2; 0% to 30% in dichloromethane dichloromethane:methanol:NH4OH (v/v) 110:10:1) , followed by further purification by preparative HPLC to give the title compound (30.2 mg, 18% yield) as a white powder. LC-MS: m/z 397.1 [MH] ^- , ESI neg.

step 3 : 2-[2-[(3a R ,7a S or 3a S ,7a R )-6- methyl -3,3a,4,5,7,7a- Hexahydro -2H- pyrrolo [2,3- c ] pyridine -1- base ] zozolo [4,5- b ] pyridine -5- base ]-5- chlorine -3- methyl - Phenol and 2-[2-[(3a S ,7a R or 3a R ,7a S )-6- methyl -3,3a,4,5,7,7a- Hexahydro -2H- pyrrolo [2,3-c] pyridine -1- base ] zozolo [4,5- b ] pyridine -5- base ]-5- chlorine -3- methyl - phenol

The above ( racemic )-5- chloro -3- methyl -2-[2-(6- methyl -3,3a,4,5,7,7a- hexahydro - 2H - pyrrolo- [ 2,3- c ] pyridin -1- yl ) oxazolo [4,5-b] pyridin -5- yl ] phenol (Example 20, step 2) by chiral SFC (column: chiral column IJ , 5 µm, 250 × 20 mm), eluent: methanol 25% + 0.2% diethylamine) were separated to obtain two enantiomers: light brown foam Example 20A (8 mg, yield 41%, First eluate, Rt = 1.46 min), m/z 399.2 [M+H] ⁺ , ESI pos; and Example 20B as light brown foam (8 mg, 41% yield, second eluate, Rt = 2.26 min) m/z 399.2 [M+H] ⁺ , ESI pos. Example 21 : 5- Chloro -2-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridin -5- yl ]- 6- fluoro -3- methyl - phenol; 2,2,2- trifluoroacetate

step A : 2-(3- chlorine -2- fluorine -5- Tolyl )-4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane

To 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4391.3 mg, 17.3 mmol, 1.0 eq) in THF (50 mL) was added 4,4'-di-tertiary-butyl-2,2'-bipyridine (139.2 mg, 0.52 mmol, 0.03 eq) and (1 ,5-cyclooctadiene)(methoxy)iridium(I) dimer (229.25 mg, 0.35 mmol, 0.02 eq), then 2-chloro-1-fluoro-4-toluene (2500.0 mg, 17.29 mmol , 1.0 eq). The above reaction mixture was stirred at 80°C for 12 hours. Then, the reaction mixture was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether:ethyl acetate=1:0 to 20:1) to obtain the title compound (4.5 g, yield 96%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.50 (dd, 1H), 7.36 (dd, 1H), 2.27 (s, 3H), 1.29 (s, 12H).

step B : 3- chlorine -2- fluorine -5- Methylphenol

Add 2-(3-chloro-2-fluoro-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.50 g, 16.6 mmol, 1.0 eq) in THF (50 mL) was added H ₂ O ₂ (9.43 g, 83.17 mmol, 5.0 eq) and stirred at 20°C for 2 hours. The above reaction solution was diluted with water (50 mL), then Na ₂ S ₂ O ₃ (16 g, 83 mmol) was added, stirred at 20°C for 20 minutes, and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by a silica gel column (petroleum ether:ethyl acetate=1:0 to 20:1) to obtain the title compound (2500 mg, yield 84%) as a yellow oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.19 (br.s, 1H), 6.77 - 6.68 (m, 2H), 2.18 (s, 3H).

step C : 3- chlorine -2- fluorine -6- iodine -5- Methylphenol

To a solution of 3-chloro-2-fluoro-5-methylphenol (1.50 g, 9.34 mmol, 1.0 eq) in toluene (30 mL) was added NaH (934.2 mg, 23.35 mmol, in mineral oil, purity 60%, 2.5 eq), then stirred at 20°C for 0.5 h, then slowly added iodine (2.13 g, 8.41 mmol, 0.9 eq) in portions at 0°C. The above reaction mixture was stirred at 20 °C for 0.5 h. The above reaction mixture was quenched with dilute hydrochloric acid (100 mL, 1 M aqueous solution) at 0°C, and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by a silica gel column (petroleum ether:ethyl acetate=1:0 to 10:1) to obtain the title compound (1.10 g, yield 41%) as yellow oil. LC-MS: m/z 284.8 [MH] ^- , ESI neg.

step D. : 1- chlorine -2- fluorine -4- iodine -3- Methoxy -5- toluene

To a solution of 3-chloro-2-fluoro-6-iodo-5-methylphenol (1.0 g, 3.49 mmol, 1.0 eq) in DMF (5 mL) was added K ₂ CO ₃ (1206.06 mg, 8.73 mmol, 2.5 eq), then MeI (0.43 mL, 6.98 mmol, 2.0 eq) was added dropwise at 0°C, then stirred at 20°C for 2 hours. The above reaction solution was diluted with water (100 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1:0 to 10:1) to obtain the title compound (700.0 mg, yield 67%) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.08 (dd, 1H), 3.95 (d, 3H), 2.42 (s, 3H).

step E. : 2-(4- chlorine -3- fluorine -2- Methoxy -6- Tolyl )-4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane

To 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (557.3 mg, 3.0 mmol, 1.5 eq) in THF (12 mL) 1-Chloro-2-fluoro-4-iodo-3-methoxy-5-toluene (600.0 mg, 2.0 mmol, 1.0 eq) was added to the solution, and then n -BuLi (1.5 mL, 3.75 mmol, 2.5 M in hexanes, 1.88 eq), then stirred at -70 °C under _N2 for 0.5 h. The above reaction solution was quenched with saturated ammonium chloride (100 mL) at 0°C, and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1:0 to 2:1) to obtain the title compound (400.0 mg, yield 67%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.89 (d, 1H), 3.91 (d, 3H), 2.30 (s, 3H), 1.39 (s, 12H).

step f : (4- chlorine -3- fluorine -2- hydroxyl -6- Tolyl ) boric acid

_2- (4-Chloro-3-fluoro-2-methoxy-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2 - To a solution of dioxaborolane (150.0 mg, 0.5 mmol, 1.0 eq) in DCM (2 mL), BBr ₃ (0.5 mL, 4.99 mmol, 10.0 eq) was added dropwise, then the mixture was heated at 25°C Stir for 2 hours. The reaction mixture was poured into 10 mL of water at 0°C. The pH was adjusted to 8 with 1M NaOH solution, then the mixture was washed with ethyl acetate (10 mL × 3), then the aqueous phase was acidified to pH = 4 with 1 N HCl solution, washed with ethyl acetate (20 mL × 3) extraction. The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (4-chloro-3-fluoro-2-hydroxy-6- tolyl)boronic acid (40 mg, 39% yield). ¹ H NMR (400 MHz, CD ₃ OD) δ 6.73 (d, 1H), 2.17 (s, 3H).

step G : 5- bromine -2- methylmercapto - zozolo [4,5- b ] pyridine

1,1'-thiocarbonyldiimidazole (5.42 g, 30.42 mmol, 1.15 eq) was added portionwise to 2-amino-6-bromopyridin-3-ol (CAS # 934758-27-7, 5.0 g, 26.45 mmol, 1.0 eq) in DMF (100 mL). The reaction mixture was stirred under nitrogen for 16 hours. Potassium carbonate (7.31 g, 52.91 mmol, 2.0 eq) was then added followed by methyl iodide (1.9 mL, 30.52 mmol, 1.15 eq) and the reaction was stirred for a further 18 hours. The reaction mixture was cooled to 0 °C and quenched by the slow addition of water (70 mL), after which a precipitate formed. The reaction mixture was filtered, and the solid was washed with water. The product was dissolved in MeCN and concentrated in vacuo, then the product was dried in a vacuum oven overnight to give the title compound (4.89 g, 68% yield) as a brown solid. LC-MS: m/z 244.9/246.9 [M+H] ⁺ , ESI pos.

step h : 5- bromine - N -[(3 R )-1- Ethyl -3- piperidinyl ] zozolo [4,5- b ] pyridine -2- amine

Triethylamine (3.3 mL, 23.7 mmol, 5.0 eq), (3 R )-1-ethylpiperidin-3-amine dihydrochloride (1.9 g, 9.47 mmol, 2.0 eq) and 5-bromo-2 -Methylhydrogenthio-oxazolo[4,5- b ]pyridine (CAS # 1149384-63-3, 1.16 g, 4.73 mmol, 1.0 eq) was dissolved in dioxane (20 mL), and the reaction The mixture was stirred at 90°C for 24 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried using a phase separator and concentrated in vacuo . The resulting residue was purified by column chromatography (silica gel, 40 g, 0% to 10% (0.7 N NH _in MeOH)/DCM) to afford the title compound (1.61 g, yield 91 %). LC-MS: m/z 325.2/327.2 [M+H] ⁺ , ESI pos.

step I : 5- chlorine -2-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-6- fluorine -3- methyl - phenol; 2,2,2- Trifluoroacetate

To (4-chloro-3-fluoro-2-hydroxy-6-tolyl)boronic acid (40 mg, 0.2 mmol, 1.0 eq) in 1,4-dioxane (2 mL) and water (0.4 mL) Add 5-bromo- N -[(3 R )-1-ethyl-3-piperidinyl]oxazolo[4,5- b ]pyridin-2-amine to the solution; 2,2,2-trifluoro Acetic acid (68.77 mg, 0.16 mmol, 0.8 eq), K ₂ CO ₃ (67.6 mg, 0.49 mmol, 2.5 eq) and Pd(dppf)Cl ₂ (28.64 mg, 0.04 mmol, 0.2 eq), then under N ₂ gas Stir at 95°C for 2 hours. The above reaction mixture was cooled to room temperature and diluted with acetonitrile (5 mL), filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (0.1% TFA, water-MeCN), then the solvent was removed by lyophilization to give the title compound (13.9 mg, 13% yield) as a white solid. LC-MS: m/z 404.9 [MH] ^- , ESI neg. Example 22 : 5- chloro -2-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridin -5- yl ]- 4- fluoro -3- methyl - phenol; 2,2,2- trifluoroacetate

step A : 6- bromine -4- chlorine -3- fluorine -2- toluidine

To a solution of 4-chloro-3-fluoro-2-toluidine (4.50 g, 28.2 mmol, 1.0 eq) in MeCN (100 mL) was added a portion of NBS (6.02 g, 33.8 mmol, 1.2 eq). The mixture was stirred at 20 °C under nitrogen atmosphere for 2 hours. The mixture was diluted with 50 mL of water, extracted with ethyl acetate (40 mL × 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether:ethyl acetate=1:0 to 10:1) to obtain the title compound (5.00 g, yield 74%) as a dark brown solid. LC-MS: m/z 238.0 [M+H] ⁺ , ESI pos.

step B : 4- chlorine -3- fluorine -6- Methoxy -2- toluidine

Add 6-bromo-4-chloro-3-fluoro-2-toluidine (3.00 g, 12.6 mmol, 1.0 eq) and CuI (2.38 g, 12.6 mmol, 1.0 eq) in DMF (60 mL) at 20°C NaOMe (9.06 g, 50.32 mmol, 4.0 eq) was slowly added to the solution. The mixture was stirred at 120°C for 3 hours. The above reaction mixture was cooled to room temperature, saturated ammonium chloride (200 mL) was added, and extracted with ethyl acetate (200 mL × 3). The combined organic extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by a silica gel column (petroleum ether:ethyl acetate=20:1 to 5:1) to obtain the title compound (900 mg, yield 38%) as a dark brown solid. LC-MS: m/z 190.1 [M+H] ⁺ , ESI pos.

step C : 2- bromine -5- chlorine -4- fluorine -1- Methoxy -3- toluene

To 4-chloro-3-fluoro-6-methoxy-2-toluidine (250.0 mg, 1.32 mmol, 1.0 eq), CuBr (37.83 mg, 0.26 mmol, 0.2 eq) and CuBr ₂ (294.5 mg , 1.32 mmol, 1.0 eq) in MeCN (5 mL) was slowly added tert -butyl nitrite (314 µL, 2.64 mmol, 2.0 eq). The mixture was stirred at 20 °C for 2 hours under nitrogen. The above reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), then the combined organic extracts were concentrated over anhydrous sodium sulfate and under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1:0 to 10:1) to obtain the title compound (150.0 mg, yield 45%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.23 (d, 1H), 3.86 (s, 3H), 2.32 (d, 3H).

step D. : 2-(4- chlorine -3- fluorine -6- Methoxy -2- Tolyl )-4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane

To a solution of 2-bromo-5-chloro-4-fluoro-1-methoxy-3-toluene (50.0 mg, 0.2 mmol, 1.0 eq) in THF (1 mL) was added 2-isopropoxy- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (91.8 mg, 0.49 mmol, 2.5 eq), then added dropwise n -BuLi (0.12 mL , 0.3 mmol, 2.5 M in hexane, 1.5 eq), then stirred at -70°C for 1 hour. The above reaction solution was quenched with saturated ammonium chloride solution (50 mL) at 0°C, and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by prep-TLC (petroleum ether:ethyl acetate=20:1, Rf=0.4) to give the title compound (40.0 mg, yield 67%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.66 (d, 1H), 3.73 (s, 3H), 2.28 (d, 3H), 1.41 (s, 12H).

step E. : ( R )-5-(4- chlorine -3- fluorine -6- Methoxy -2- Tolyl )- N -(1- Ethylpiperidine -3- base ) zozolo [4,5- b ] pyridine -2- amine

To 2-(4-chloro-3-fluoro-6-methoxy-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane ( 30.0 mg, 0.1 mmol, 1.0 eq) to a solution in 1,4-dioxane (1 mL) and water (0.2 mL) was added ( R )-6-bromo- N- (1-ethylpiperidine- 3-yl)-3 H -pyrrolo[2,3- b ]pyridin-2-amine (43.8 mg, 0.1 mmol, 1.0 eq), CsF (37.9 mg, 0.25 mmol, 2.5 eq) and Xphos Pd G3 (16.92 mg, 0.02 mmol, 0.2 eq), and then the above reaction mixture was stirred at 90°C for 1 hour under N ₂ gas. The above reaction solution was diluted with water (100 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by prep-TLC (dichloromethane:methanol=10:1, Rf=0.1) to give the title compound (40.0 mg, yield 63%) as yellow oil. LC-MS: m/z 419.0 [M+H] ⁺ , ESI pos.

step f : 5- chlorine -2-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-4- fluorine -3- methyl - phenol; 2,2,2- Trifluoroacetate

To ( R )-5-(4-chloro-3-fluoro-6-methoxy-2-methylphenyl) -N- (1-ethylpiperidin-3-yl)oxazolo[ To a solution of 4,5- b ]pyridin-2-amine (30.0 mg, 0.07 mmol, 1.0 eq) in dichloromethane (1 mL) was added BBr ₃ (178.8 mg, 0.72 mmol, 10.0 eq), then at 20 °C and stirred for 1 hour. The above reaction mixture was quenched with water (0.5 mL) at 0°C, diluted with methanol (1 ml), then the pH was adjusted to about 7 with ammonium hydroxide, and then reversed phase chromatography (C18, 0.1% TFA, water-ACN) followed by removal of solvent by lyophilization to give the title compound (10.6 mg, 28% yield) as a white solid. LC-MS: m/z 405.0 [M+H] ⁺ , ESI pos. Example 23 : 5- chloro -2-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridin -5- yl ]- 3- Hydroxy - benzonitrile

step A : 2- bromine -5- chlorine -3- hydroxyl - Benzonitrile

N -bromosuccinimide (3.60 g, 20.2 mmol, 1.04 eq) was added to 3-chloro-5-hydroxybenzonitrile (CAS # 473923-97-6, 3.0 g, 19.5 mmol, 1.0 eq) and diisopropylamine (1.0 mL, 7.14 mmol, 0.37 eq) in DCM (50 mL), and the reaction was allowed to return to room temperature and stirred for another 3 days. The solvent was concentrated in vacuo, and the crude product was purified by column chromatography (silica gel, 330 g, DCM) to give the title compound (738 mg, 16% yield) as a white solid. LC-MS: m/z 229.9 [MH] ^- , ESI neg.

step B : 2- bromine -5- chlorine -3- Methoxy - Benzonitrile

Potassium carbonate (875.0 mg, 6.33 mmol, 2.02 eq) was added to 2-bromo-5-chloro-3-hydroxy-benzonitrile (730.0 mg, 3.14 mmol, 1.0 eq) in acetone (8 mL) at room temperature The solution was stirred, and the reaction was stirred for 5 min. Iodomethane (300.0 µL, 4.82 mmol, 1.53 eq) was then added, and the reaction was stirred for a further 16 hours. The reaction was concentrated in vacuo, then diluted with DCM (50 mL) and water (50 mL). The organic layer was separated and the aqueous phase was re-extracted with DCM (2 x 50 mL). The combined organic layers were dried over MgSO ₄ and concentrated in vacuo to give the title compound (752.0 mg, 92% yield) as a white solid which was used without further purification. m/z not observed by LC-MS. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.72 (d, 1H), 7.57 (d, 1H), 3.95 (s, 3H).

step C : 5- chlorine -3- Methoxy -2-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base ) Benzonitrile

Isopropylmagnesium chloride-LiCl complex (1.3M solution) (5.85 mL, 7.61 mmol, 2.5 eq) was added dropwise to 2-bromo-5-chloro-3-methoxy-benzonitrile (750.0 mg , 3.04 mmol, 1.0 eq) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.1 mL, 15.21 mmol, 5.0 eq) In a stirred solution in THF (30 mL). The reaction was brought to room temperature and stirred for 16 hours. The reaction mixture was concentrated in vacuo, then diluted with water (100 mL) and DCM (100 mL), and the organic layer was separated. The aqueous layer was re-extracted with DCM (2 × 100 mL), and the combined organic layers were washed with water (2 × 100 mL) and brine (100 mL), then dried over MgSO ₄ and concentrated in vacuo to give shallow The title compound as a yellow waxy solid (914.6 mg, 72% yield). LC-MS m/z 210.2 [M-BPin] ^- , ESI neg.

step D. : 5- chlorine -2-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- Methoxy - Benzonitrile

5-Bromo-N-[(3R)-1-ethyl-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine ( Example 21 , Step H ) (200 mg, 0.62 mmol, 0.96 eq), 5-chloro-3-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl Nitrile (250.0 mg, 0.64 mmol, 1.0 eq), cesium carbonate (620.0 mg, 1.9 mmol, 2.98 eq) and Xphos Pd G3 (55.0 mg, 0.06 mmol, 0.1 eq) in 1,4-dioxane (4.5 mL) The mixture in water (0.5 mL) was degassed with nitrogen for 5 minutes and then heated to 90°C for 1 hour. The reaction was cooled to room temperature, concentrated, and purified by silica gel column chromatography (40 g, 0% to 10% MeOH (0.7M NH ₃ )/DCM) to give the title compound (131 mg, Yield 17%). LC-MS m/z 412.3 [M+H] ⁺ , ESI pos.

step E. : 5- chlorine -2-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-3- hydroxyl - Benzonitrile

_BBr3 (1M in DCM) (0.98 mL, 0.98 mmol, 10.23 eq) was added dropwise to 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl at 0 °C ]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-benzonitrile (131.0 mg, 0.1 mmol, 1.0 eq) and tetrabutylammonium iodide (123.34 mg, 0.33 mmol, 3.5 eq) in a stirred solution in DCM (5 mL), and the reaction was allowed to return to room temperature. After 24 hours, the reaction was cooled to 0 °C and another equivalent of _BBr3 (IM in DCM) (0.98 mL, 0.98 mmol, 10.23 eq) was added. The reaction was allowed to return to room temperature, then stirred for an additional 24 hours. The reaction was quenched by dropwise addition to a stirred solution of _NH3 in MeOH (100 mL, 7M) at 0 °C. The solvent was concentrated in vacuo and the resulting residue was taken up in DCM (20 mL) and water (20 mL). The aqueous phase was adjusted to about pH 12 with aqueous NaOH (2M) and the organic phase was separated. The aqueous phase was re-extracted with DCM (2 x 20 mL). The combined organic layers were dried over MgSO ₄ , concentrated in vacuo, and purified by silica gel column chromatography (40 g cartridge, 0% to 5% MeOH (7M NH ₃ )/DCM). The product was then taken up in DCM (5 mL) and washed with water (5 x 5 mL), then dried by passing through a phase separator and concentrated in vacuo to give the title compound as an off-white solid (5.0 mg, yielding rate of 12%). LC-MS m/z 398.3 [M+H] ⁺ , ESI pos, m/z 396.2 [MH] ^- , ESI neg. Example 24 : 5- chloro -2-[2-[[(3R)-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridin -5- yl ]-3 -( methoxymethyl ) phenol ; 2,2,2- trifluoroacetate

step A : 5- chlorine -3- hydroxyl -2- iodine - Benzaldehyde

To a mixture of 3-chloro-5-hydroxybenzaldehyde (7.5 g, 47.9 mmol, 1.0 eq) in DMF (80 mL) was added NaH (2299.3 mg, 95.8 mmol, 2.0 eq) at 0 °C under _N2 , stirred for 30 minutes, then added I ₂ (12157.98 mg, 47.9 mmol, 1.0 eq) in portions, and stirred at 25°C for 15.5 hours. The mixture was poured into water (150 mL), and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Then, the mixture was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 10/1) and by preparative HPLC (NH ₃ —H ₂ O), and lyophilized, To obtain 5-chloro-3-hydroxy-2-iodo-benzaldehyde (1300 mg, 10% yield) as a light green solid. ¹ H NMR (400 MHz, DMSO-d6) δ 11.45 - 11.27 (m, 1H), 10.03 - 9.98 (m, 1H), 7.21 - 7.19 (m, 1H), 7.17 - 7.14 (m, 1H)

step B : 5- chlorine -2- iodine -3-(2- Trimethylsilylethoxymethoxy ) Benzaldehyde

A mixture of Cs ₂ CO ₃ (2249.34 mg, 6.9 mmol, 1.5 eq) and 5-chloro-3-hydroxy-2-iodo-benzaldehyde (1300.0 mg, 4.6 mmol, 1.0 eq) in DMF (2 mL) was decomposed gas, and purged with N ₂ three times, and stirred for another 30 minutes. Then, a batch of SEMCl (1150.97 mg, 6.9 mmol, 1.5 eq) was added to the mixture. The mixture was stirred at 25°C for 2 hours. The mixture was poured into water (50 mL), and extracted with ethyl acetate (40 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1200 mg, 63% yield) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 7.48 (d, 1H), 7.38 (d, 1H), 5.46 (s, 2H), 3.79 - 3.73 (m, 2H), 0.92 -0.88 (m, 2H), -0.04 (s, 9H).

step C : [5- chlorine -2- iodine -3-(2- Trimethylsilylethoxymethoxy ) Phenyl ] Methanol

Sodium borohydride (132.0 mg, 3.49 mmol, 1.2 eq) was added in small portions to 5-chloro-2-iodo-3-(2-trimethylsilylethoxymethoxy)benzaldehyde (1200.0 mg, 2.91 mmol, 1.0 eq) in methanol (12 mL) and water (1.2 mL). The mixture was stirred at 25 °C for 3 h, then diluted with water (20 mL). The mixture was poured into water (15ml) and extracted with ethyl acetate (30mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give [5-chloro-2-iodo-3-(2-tris Methylsilylethoxymethoxy)phenyl]methanol (870 mg, 72% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.13 (d, 1H), 7.09 (d, 1H), 5.59 (t, 1H), 5.36 (s, 2H), 4.40 (d, 2H), 4.03 ( q, 1H), 3.74 (t, 2H), 1.99 (s, 2H), 1.17 (t, 2H), 0.88 (t, 2H), -0.04 (s, 9H).

step D. : 2-[[5- chlorine -2- iodine -3-( Methoxymethyl ) Phenoxy ] Methoxy ] Ethyl - Trimethyl - Silane

[5-Chloro-2-iodo-3-(2-trimethylsilylethoxymethoxy)phenyl]methanol (870.0 _mg , 2.1 mmol, 1.0 eq) and To a mixture of NaH (60.41 mg, 2.52 mmol, 1.2 eq) in THF (8 mL) was added a portion of MeI (0.13 mL, 2.1 mmol, 1.0 eq) and stirred for 5 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 0/1 to 5/1), concentrated under reduced pressure to give the title compound as a colorless oil (800 mg, yield 89 %). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.11 (d, 1H), 7.07 (d, 1H), 5.32 (s, 2H), 4.86 (s, 7H), 4.44 (s, 2H), 3.81 (t , 2H), 3.47 (s, 3H), 0.94 (t, J = 8.0 Hz, 2H), 0.01 (s, 9H).

step E. : 2-[[5- chlorine -3-( Methoxymethyl )-2-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base ) Phenoxy ] Methoxy ] Ethyl - Trimethyl - Silane

₂ -[[5-Chloro-2-iodo-3-(methoxymethyl)phenoxy]methoxy]ethyl-trimethyl-silane (800.0 mg, 1.87 mmol, 1.0 eq) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (624.87 mg, 3.36 mmol, 1.8 eq) in To a solution in THF (5 mL) was added dropwise nBuLi (1.12 mL, 2.8 mmol, 1.5 eq) and stirred at -60°C for 30 minutes. The mixture was poured into NH4Cl solution (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EA 10:1) to give the title compound (260 mg, 33% yield) as a colorless oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.02 (d, 1H), 6.93 (s, 1H), 5.22 (s, 2H), 4.43 (s, 2H), 3.84 - 3.74 (m, 2H), 3.30 (s, 3H), 1.37 (s, 12H), 0.98 - 0.92 (m, 2H), 0.00 (s, 9H).

step f : 5- chlorine -3-( Methoxymethyl )-2-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base ) phenol

2-[[5-chloro-3-(methoxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- A solution of phenoxy]methoxy]ethyl-trimethyl-silane (65.0 mg, 0.15 mmol, 1.0 eq) and TFA (0.5 mL) in DCM (0.25 mL) was stirred at 25°C for 12 hours. The mixture was poured into water (10ml) and extracted with EA (10mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=0/1 to 1/0) to obtain the title compound (45.0 mg, yield 99%) as a colorless oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 6.71 (d, 1H), 6.67 (d, 1H), 4.38 (s, 2H), 3.38 (s, 3H), 1.20 (s, 12H).

step G : 5- chlorine -2-[2-[[(3R)-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3-( Methoxymethyl ) phenol; 2,2,2- Trifluoroacetate

K ₂ CO ₃ (23.14 mg, 0.17 mmol, 2.5 eq), 5-chloro-3-(methoxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)phenol (20.0 mg, 0.07 mmol, 1.0 eq) and 5-bromo-N-[(3 R )-1-ethyl-3-piperidinyl]oxazole [4,5-b]pyridin-2-amine; 2,2,2-trifluoroacetic acid (38.3 mg, 0.09 mmol, 1.3 eq) in 1,4-dioxane (1 mL) and water (0.200 mL ) and three times with N ₂ , and XphosPdG3 (5.63 mg, 0.01 mmol, 0.1 eq) was added to the mixture. The mixture was heated at 100 °C for 2 h under microwave irradiation. The mixture was concentrated under reduced pressure and analyzed by reverse phase flash chromatography (0.1% TFA) and preparative HPLC (Method Column 3_Phenomenex Luna C ₁₈ 75×30mm×3 μm; conditioned water (TFA)-CAN; start B 16 at the end; B 46 at the end; Gradient time (min) 8; 100% B hold time (min) 2; Flow rate (mL/min) 25; Injection 1 HPLC 99), after lyophilization, the title Compound (TFA salt) (10.95 mg, 31% yield). LCMS: m/z 417.1 [M+H]+, ESI pos. Example 25 : 4-[2-[[(3R)-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridin -5- yl ]-3- hydroxyl -5 -Methyl - benzonitrile _

step A : 4- Amino -3- Methoxy -5- methyl - Benzonitrile

Two batches were run in parallel. To a solution of 4-bromo-2-methoxy-6-methyl-aniline (25.0 g, 115 mmol, 1.0 eq) in DMF (250 mL) was added Zn(CN) ₂ (13.5 g, 115 mmol, 7.34 mL, 1.00 eq) and Pd(PPh ₃ ) ₄ (66.8 g, 57.8 mmol, 0.50 eq). The reaction mixture was stirred at 100°C for 12 hours. The reaction mixture was poured into H ₂ O (1.50 L), and extracted with ethyl acetate (1.00 L×3). The organic phase was washed with brine (1.00 L x 3), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue, which was analyzed by column chromatography (SiO ₂ , petroleum ether /ethyl acetate=100/1 to 0/1), to obtain the title compound (28.0 g, yield 75%) as a yellow solid.

step B : 4- bromine -3- Methoxy -5- methyl - Benzonitrile

To a solution of CuBr (46.4 g, 323 mmol, 9.86 mL, 1.50 eq) in MeCN (180 mL) was added t-BuONO (33.3 g, 323 mmol, 38.5 mL, 1.50 eq) and stirred at 65 °C. Then a solution of 4-amino-3-methoxy-5-methyl-benzonitrile (35.0 g, 215 mmol, 1.00 eq) in MeCN (180 mL) at 65 °C was added. The mixture was stirred at 65°C for 3.5 hours. After cooling to room temperature, saturated Na ₂ SO ₃ (400 mL) and saturated aqueous NH ₄ Cl (200 mL) were added to the mixture, and extracted with ethyl acetate (500 mL×3). The organic phase was washed with brine (500 mL x 2), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 0/1, _Rf = 0.75) to give the title compound (20.7 g, 42% yield) as a white solid ).

step C : 3- Methoxy -5- methyl -4-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base ) Benzonitrile

To a solution of 4-bromo-3-methoxy-5-methyl-benzonitrile (18.0 g, 79.6 mmol, 1.00 eq) in DMF (180 mL) was added B ₂ Pin ₂ (30.3 g, 119 mmol, 1.50 eq) and AcOK (35.1 g, 358 mmol, 4.50 eq). The mixture was stirred at 20 °C for 0.5 h, and Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (13.0 g, 15.9 mmol, 0.20 eq) was added. The mixture was stirred at 100°C for 12 hours. After cooling to room temperature, the mixture was filtered through celite, diluted with H ₂ O (500 mL), and extracted with ethyl acetate (800 mL×3). The organic phase was washed with brine (800 mL x 3), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 1/1, _Rf = 0.30) to give the title compound (18.0 g, 83% yield) as a white solid ).

step D. : (4- cyano -2- hydroxyl -6- methyl - Phenyl ) boric acid

3-Methoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (17.0 g , 96.0 mmol, 1.00 eq) in DCM (170 mL) was cooled to 0°C, and BBr ₃ (38.9 g, 155 mmol, 2.50 eq) was added dropwise at 0°C. The mixture was stirred at 0 °C for 0.5 h. The mixture was poured into H ₂ O (200 mL), filtered, and the filter cake was collected and triturated with ethyl acetate (20 mL) to give the title compound (4.67 g, 42% yield) as a gray solid. LCMS: m/z 178.1 [M+H] ⁺ , ESI pos.

step E. : 4-[2-[[(3R)-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- hydroxyl -5- methyl - Benzonitrile

The above (5-chloroazolo[4,5-b]pyridin-2-yl)-[(3R)-1-ethyl-3-piperidinyl]amine (241 mg, 858.4 umol, 1.0 eq) , (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid above ( Example 25 , Step D ) (280.71 mg, 1.46 mmol, 1.7 eq) and cesium carbonate (839.07 mg, 2.58 mmol, 3.0 eq ) was dissolved in 1,4-dioxane (5.9 mL) and water (1.48 mL). Argon was then bubbled through the mixture for 2 min before the addition of catalyst methanesulfonate (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl )(2'-Amino-1,1'-biphenyl-2-yl)palladium(ii) (XPhos Pd G3) (108.99 mg, 128.76 umol, 0.15 eq). The sealed tube was stirred at 100°C for 16 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate (2 x 80 mL) and half-saturated aqueous ammonium chloride (80 mL). The organic layer was washed with water (80 mL) and brine (80 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography ( _Si02 ; 0% to 50% ethyl acetate in heptane; then ethyl acetate:methanol 9:1 (v/v)), followed by ethyl acetate/ Heptane crystallized to give the title compound (135 mg, 41% yield) as a pale yellow solid. LC-MS: 378.2 [M+H] ⁺ , ESI pos. Example 26 : 3- Hydroxy -5- methyl -4-[2-[[(3 R )-1- methyl -3- piperidinyl ] amino ] oxazolo [4,5-b ] pyridine- 5- yl ] benzonitrile

step 1 : 3- hydroxyl -5- methyl -4-[2-[[(3 R )-1- methyl -3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ] Benzonitrile

The above 5-chloro- N -[(3R)-1-methyl-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine ( Example 15 , Step 1) (112 mg, 0.420 mmol, 1.0 eq), (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid ( Example 25 , step D ) (137.3 mg, 0.71 mmol, 1.7 eq) and potassium carbonate (261.2 mg, 1.9 mmol, 4.5 eq) was dissolved in 1,4-dioxane (3 mL) and water (1.5 mL). Argon was then bubbled through the mixture for 2 minutes before the addition of the catalyst 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(ii) dichloromethane complex (51.4 mg, 0.063 mmol, 0.15 eq). The sealed tube was stirred at 90°C for 16 hours. Then, the reaction mixture was extracted with ethyl acetate (2 x 30 mL) and half-saturated aqueous ammonium chloride (30 mL). The organic layer was washed with water (30 mL) and brine (30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography ( _Si02 ; 0% to 50% ethyl acetate in heptane; then ethyl acetate:methanol 9:1 (v/v)), followed by ethyl acetate/ Heptane crystallized to give the title compound (51 mg, 32% yield) as an off-white solid. LC-MS: 364.2 [M+H] ⁺ , ESI pos. Examples 27 , 27a and 27b : ( rac )-3- hydroxy -5- methyl -4-[2-(6- methyl - 3,3a , 4,5,7,7a - hexahydro- 2 H - pyrrolo [2,3-c] pyridin -1- yl ) oxazolo [4,5-b] pyridin -5- yl ] benzonitrile and corresponding enantiomers 27A and 27B

step 1 : 5- chlorine -2-(6- methyl -3,3 a ,4,5,7,7 a - Hexahydro -2H- pyrrolo [2,3- c ] pyridine -1- base ) zozolo [4,5- b ] pyridine

To 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 260 mg, 1.23 mmol, 1.00 eq) and 6-methyl-1,2 ,3,3 a ,4,5,7,7 a -octahydropyrrolo[2,3- c ]pyridine (CAS # 1443980-22-0, 224 mg, 1.60 mmol, 1.30 eq) in 1,4- To a mixture in dioxane (4.0 mL) and N -methyl-2-pyrrolidone (2.0 mL) was added triethylamine (374 mg, 0.515 mL, 3.69 mmol, 3.00 eq). The reaction mixture was heated and stirred at 120°C for 2 hours and at 150°C for 20 hours. The reaction mixture was cooled to room temperature and extracted with a mixture of ethyl acetate:MTBE (1:1) and water. The aqueous layer was back extracted with a mixture of ethyl acetate:MTBE (1:1). The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was absorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 10% methanol in dichloromethane) to give the title compound (313 mg , yield 86%). LC-MS: m/z 293.1 [M+H] ⁺ , ESI pos.

step 2 : ( Racemization )-3- hydroxyl -5- methyl -4-[2-(6- methyl -3,3a,4,5,7,7a- Hexahydro -2H- pyrrolo [2,3-c] pyridine -1- base ) zozolo [4,5-b] pyridine -5- base ] Benzonitrile

5-Chloro-2-(6-methyl- 3,3a , 4,5,7,7a -hexahydro- 2H -pyrrolo[2,3- c ]pyridine- 1-yl) oxazolo[4,5- b ]pyridine ( Example 20 , step 1 ) (160 mg, 0.54 mmol, 1.00 eq) and (4-cyano-2-hydroxy-6-methyl-phenyl ) boronic acid ( Example 25 , Step D ) (208 mg, 1.08 mmol, 2.00 eq) To a mixture of 1,4-dioxane (6.0 mL) and water (3.0 mL) was added potassium carbonate (359 mg, 2.60 mmol , 4.80 eq). Argon was bubbled through the reaction mixture for three minutes. Then, 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(ii)dichloromethane complex (88 mg, 0.11 mmol, 0.20 eq) was added under stirring at room temperature. The tube was sealed and stirred at 100°C for 20 hours. The reaction mixture was extracted with ethyl acetate and half-saturated aqueous _NH4Cl . The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was absorbed on ISOLUTE HM-N and analyzed by flash chromatography (silica gel, 40 g, gradient: 0% to 100% in dichloromethane (dichloromethane:methanol:NH ₄ OH 110:10: 1)) Purification to give the title compound (100 mg, 43% yield, 90% purity) as dark brown foam. LC-MS: m/z 390.2 [M+H] ⁺ , ESI pos.

step 3 : 4-[2-[(3 aS ,7 aR or 3 aR ,7 aS )-6- methyl -3,3 a ,4,5,7,7 a - Hexahydro -2H- pyrrolo [2,3- c ] pyridine -1- base ] zozolo [4,5-b] pyridine -5- base ]-3- hydroxyl -5- methyl - Benzonitrile and 4-[2-[(3 aR ,7 aS or 3 aS ,7 aR )-6- methyl -3,3 a ,4,5,7,7 a - Hexahydro -2H- pyrrolo [2,3- c ] pyridine -1- base ] zozolo [4,5- b ] pyridine -5- base ]-3- hydroxyl -5- methyl - Benzonitrile

Racemate ( rac )-3-hydroxy-5-methyl-4-[2-(6-methyl- 3,3a , 4,5,7,7a -hexahydro- 2H -pyrrolo[2,3- c ]pyridin-1-yl)oxazolo[4,5-b]pyridin-5-yl]benzonitrile ( example 20 , step 2 ) by chiral SFC (column: Chiralpak IJ, eluent B: 20% methanol + 0.2% diethylamine) were separated to obtain two enantiomers: Light brown foamy example 27A (eluted first, retention time = 1.31 minutes) (35 mg, Yield 38%), LC-MS: m/ z 390.2 [M+H] ⁺ , ESI pos; and light brown foam Example 27B (second eluate, retention time = 1.94 min) (28 mg, yield 30%). LC-MS: m/z 390.2 [M+H] ⁺ , ESI pos. Example 28 : 4-[2-[[(3R,5S)-1- ethyl -5- hydroxyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridin -5- yl ] -3- Hydroxy -5- methyl - benzonitrile; formate

step 1 : (3R,5S)-3-[(5- Chlorazolo [4,5- b ] pyridine -2- base ) Amino ]-5- hydroxyl - piperidine -1- Tertiary butyl formate

To the above-mentioned 1,4-dioxane (3 mL) and 5- chloro -2-(methylthio)oxazolo[4,5-b ]pyridine (CAS # 1783370-92-2, 491 mg, 2.32 mmol, 1.0 eq) was added (3 R ,5 S )-3-amino-5-hydroxy-piperidine-1-carboxylic acid tertiary butyl ester ( 653.6 mg, 3.02 mmol, 1.3 eq), followed by triethylamine (423.4 mg, 583.2 µL, 4.18 mmol, 1.8 eq). The light brown solution was stirred at 150°C for 16 hours in a sealed tube. Then, the reaction was quenched with water (5 mL) and extracted with ethyl acetate (2 x 80 mL). The organic layer was washed with brine (80 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (ISCO, 25 g SiO2; 0% to 50% ethyl acetate in heptane; then ethyl acetate:methanol 9:1 (v/v)) to give shallow Yellow foam (3R,5S)-3-[(5-Chloroxazolo[4,5-b]pyridin-2-yl)amino]-5-hydroxy-piperidine-1-carboxylic acid tertiary butyl ester (441 mg, 49% yield). LC-MS: m/z 369.2 [M+H] ⁺ , ESI pos.

step 2 : (3 S ,5 R )-5-[(5- Chlorazolo [4,5-b] pyridine -2- base ) Amino ] piperidine -3- alcohol; hydrochloride

(3 R ,5 S )-3-[(5-chloroazolo[4,5- b ]pyridin-2-yl)amino]-5-hydroxy-piperidine-1-carboxylic acid tris at room temperature To a solution of butyl ester (441 mg, 1.2 mmol, 1.0 eq) in DCM (10 mL) and methanol (5 mL) was added dropwise 4 M HCl in 1,4-dioxane (3.59 g, 3.0 mL , 12 mmol, 10 eq). The reaction mixture was stirred at 23°C for 16 hours. The reaction mixture was concentrated in vacuo to give crude (3S,5R)-5-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]piperidine as a light yellow foam -3-ol; hydrochloride salt (415 mg, 102% yield), which was used in the next step without further purification. LC-MS: m/z 269.1 [M+H] ⁺ , ESI pos.

step 3 : (3S,5R)-5-[(5- Chlorazolo [4,5-b] pyridine -2- base ) Amino ]-1- Ethyl - piperidine -3- alcohol

Under cooling in an ice bath, to (3S, 5R)-5-[(5-chloroazolo[4,5-b]pyridin-2-yl)amino]piperidin-3-ol; hydrochloride ( 414 mg, 1.22 mmol, 1.0 eq) in dry DCM (16.9 mL) was added acetaldehyde (134.5 mg, 172 uL, 3.05 mmol, 2.5 eq) followed by sodium acetate (250 mg, 3.05 mmol, 2.5 eq). Sodium triacetyloxyborohydride (466 mg, 2.2 mmol, 1.8 eq) was added at 0 °C. The reaction mixture was stirred at 0 °C for 5 minutes and at room temperature for 3 hours. Then, the reaction mixture was carefully basified with aqueous NaHCO ₃ (25 mL) and extracted with dichloromethane (3×60 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 24 g, 0% to 10% methanol in dichloromethane) to give the title compound (187 mg, Yield 52%). LC-MS: m/z 297.1 [M+H] ⁺ , ESI pos.

step 4 : 4-[2-[[(3R,5S)-1- Ethyl -5- hydroxyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- hydroxyl -5- methyl - Benzonitrile; formate

(3S,5R)-5-[(5-Chloroxazolo[4,5-b]pyridin-2-yl)amino]-1-ethyl-piperidin-3-ol (example 28, step 3) (55 mg, 166.8 umol, 1.0 eq), (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid ( Example 25 , Step D ) (64.2 mg, 333.6 umol, 2.0 eq), Potassium carbonate (103.7 mg, 750.6 umol, 4.5 eq) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(ii) dichloromethane complex (20.43 mg, 25.0 umol, 0.15 eq) A mixture in 1,4-dioxane (2 mL) and water (1 mL) was flushed with argon and stirred at 100°C for 16 hours. The reaction mixture was extracted with ethyl acetate (2 x 20 mL) and half-saturated aqueous ammonium chloride (20 mL). The organic layer was washed with water (30 mL) and brine (30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 100% in DCM (DCM:methanol: _NH4OH 110:10:1)), It was then purified by preparative HPLC (column: YMC-Triart C18, 12 nm, 5 µm, 100 × 30 mm, gradient: 5% to 50% MeCN in water+0.1% HCOOH) to give white amorphous The title compound was lyophilized as a solid (12 mg, 16% yield). LC-MS: m/z 392.2 [MH] ^- , ESI neg. Example 29 : ( racemic )-4-[2-(1,2,3,5,6,7,8,8a -swainsonin -8- ylamino ) oxazolo [4,5- b ] pyridin -5- yl ]-3- hydroxy -5- methyl - benzonitrile

step 1 : ( Racemization )-(5- Chlorazolo [4,5-b] pyridine -2- base )- Indazidine -8- base - amine

5-Chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 200 mg, 947 umol, 1.0 eq) and rac-( 8S,8aS)-octahydro-8-indazinamine-dihydrochloride (262.4 mg, 1.23 mmol, 1.3 eq) in 1,4-dioxane (1.5 mL) and N-methyl-2-pyrrolidine To a suspension in ketone (1.5 mL) was added triethylamine (383 mg, 528 uL, 3.8 mmol, 4.0 eq) dropwise. The brown suspension was sealed and heated at 120°C for 16 hours. The dark orange-brown reaction mixture was cooled to room temperature and extracted twice with ethyl acetate:tBME (v/v) 1:1 (2 × 50 mL). The organic layer was washed with water (20 mL) and brine (20 mL). The aqueous layer was back extracted with ethyl acetate:tBME (v/v) 1:1 (50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and flash chromatographed ( _Si02 ; gradient: 0% to 10% methanol in DCM) to afford the title compound (64 mg, 21%) as a light brown solid . LC-MS: m/z 293.1 M+H] ⁺ , ESI pos.

step 2 : ( Racemization )-4-[2-(1,2,3,5,6,7,8,8a- Swainsonine -8- Amino ) zozolo [4,5- b ] pyridine -5- base ]-3- hydroxyl -5- methyl - Benzonitrile

( racemic )-(5-Chloroxazolo[4,5- b ]pyridin-2-yl)-indolazin-8-yl-amine (64 mg, 0.2 mmol, 1.0 eq) and (4 -cyano-2-hydroxy-6-methyl-phenyl)boronic acid ( Example 25 , Step D ) (69.6 mg, 394 umol, 2.0 eq) was dissolved in 1,4-dioxane (2 mL) and water ( 1 mL), and potassium carbonate (122.4 mg, 885.4 umol, 4.5 eq) was added. Then, the mixture was flushed with argon three times, and then 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(ii) dichloromethane complex (24.1 mg, 29.51 umol, 0.15 eq). The dark red reaction suspension was sealed and stirred at 100°C for 16 hours. Then, the reaction mixture was cooled to room temperature and extracted with DCM (2 x 20 mL) and saturated aqueous ammonium chloride (20 mL). The organic layer was washed with water (10 mL) and brine (10 mL). The aqueous layer was back extracted with DCM (20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was taken up on ISOLUTE HN-M and purified by flash chromatography (SiO2; 0% to 60% DCM:methanol: _NH4OH (v/v) 110:10:1 in DCM), And further purified by crystallization (dissolved in heptane:ethyl acetate (v/v) 1:1; powdered and evaporated) to afford the title compound (27 mg, 35%) as a pink solid. LC-MS: m/z 390.3 [M+H] ⁺ , ESI pos. Example 30 : 3-( Difluoromethyl )-2-[2-[[(3R)-1- methyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridine -5 -yl ]-5-( trifluoromethyl ) phenol; 2,2,2 - trifluoroacetate

step A : 3- hydroxyl -N- Methoxy -N- methyl -5-( Trifluoromethyl ) benzamide

To 3-hydroxy-5-(trifluoromethyl)benzoic acid (3.00 g, 14.55 mmol, 1.0 eq) and O,N-dimethylhydroxylamine HCl (1703.59 mg, 17.47 mmol, 1.2 eq) in DMF ( 30 mL) was added DIEA (5880.07 mg, 58.22 mmol, 4.0 eq), EDCI (4169.9 mg, 21.83 mmol, 1.5 eq) and HOBt (1571.9 mg, 11.64 mmol, 0.8 eq), and the mixture was heated at 25°C Stir for 2 hours. The reaction mixture was quenched by 30 mL of water, then extracted with EtOAc (40 mL × 3), washed with brine (30 mL × 2), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure . The residue was purified by column (PE:EtOAc = 10:1 to 3:1) to give the title compound (2500 mg, 69% yield) as a white solid. LC-MS: m/z 250.0 [M+H] ⁺ , ESI pos.

step B : 3- hydroxyl -2- iodine - N - Methoxy - N - methyl -5-( Trifluoromethyl ) benzamide

To a mixture of 3-hydroxy- N -methoxy- N -methyl-5-(trifluoromethyl)benzamide (6.4 g, 25.7 mmol, 1.0 eq) in toluene (65 mL) at 0°C NaH (2.05 g, 51.37 mmol, 2.0 eq) was added, and the mixture was stirred at 0°C for 10 minutes, then I ₂ (5.2 g, 20.55 mmol, 0.8 eq) was added to the mixture, and the mixture was stirred at 25°C Stir for 12 hours. The reaction mixture was quenched by 20 mL of water, then extracted with EA (30 mL × 3), washed with brine (40 mL × 2), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure , to obtain a yellow solid. The solid was purified by column (PE:EA = 20:1 to 10:1) to give the title compound (3200 mg, 33% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.07 (s, 1H), 7.05 (s, 1H), 3.52 (s, 3H), 3.38 (s, 3H).

step C : 3-( Benzyloxy )-2- iodine -N- Methoxy -N- methyl -5-( Trifluoromethyl ) benzamide

To 3-hydroxy-2-iodo- N -methoxy- N -methyl-5-(trifluoromethyl)benzamide (3.20 g, 8.53 mmol, 1.0 eq) in DMF (35 mL) K ₂ CO ₃ (2354.7 mg, 17.06 mmol, 2.0 eq) and BnBr (2.18 g, 12.8 mmol, 1.5 eq) were added to the solution, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched by 10 mL, extracted with EA (20 mL × 3), washed with brine (20 mL × 2), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to obtain A yellow solid was obtained. The solid was purified by column (PE: EA = 20:1 to 10:1) to give 3-(benzyloxy)-2-iodo-N-methoxy-N-methyl- 5-(Trifluoromethyl)benzamide (3.50 g, 88% yield). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.53 (d, 3H), 7.41 - 7.38 (m, 3H), 7.35 - 7.31 (m, 2H), 7.27 (s, 1H), 7.23 (s, 1H) , 5.28 (s, 2H), 3.91 (s, 1H), 3.51 (s, 3H), 3.39 (s, 3H), 3.12 (s, 1H).

step D. : (3-( Benzyloxy )-2- iodine -5-( Trifluoromethyl ) Phenyl ) Methanol

3-(Benzyloxy)-2-iodo- N -methoxy- N -methyl-5-(trifluoromethyl)benzamide (3.50 g, 7.52 mmol, 1.0 eq) at -60°C To a mixture in THF (40 mL) was added DIBAL-H (22.57 mL, 22.57 mmol, 3.0 eq) dropwise, and the mixture was stirred at -60°C for 3 hours. The reaction mixture was added dropwise to 20 mL saturated NH ₄ Cl solution, then extracted by EA (20 mL × 3), washed with brine (20 mL × 2), filtered, and the filtrate was concentrated under reduced pressure to obtain A yellow solid was obtained. The solid was purified by column (PE:EA = 20:1 to 10:1) to give (3-(benzyloxy)-2-iodo-5-(trifluoromethyl)phenyl ) methanol (1800 mg, 59% yield). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.45 - 7.40 (m, 3H), 7.31 - 7.27 (m, 2H), 7.24 - 7.20 (m, 1H), 7.10 (d, 1H), 5.16 (s, 2H).

step E. : 3-( Benzyloxy )-2- iodine -5-( Trifluoromethyl ) Benzaldehyde

To a mixture of 3-(benzyloxy)-2-iodo-5-(trifluoromethyl)benzaldehyde (1800.0 mg, 4.41 mmol, 1.0 eq) in DCM (20 mL) was added MnO ₂ (5524.15 mg, 22.05 mmol, 5.0 eq), and then the mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 3-(benzyloxy)-2-iodo-5-(trifluoromethyl)benzaldehyde (1500 mg, 84% yield) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 10.21 (m, 1H), 7.56 - 7.52 (m, 3H), 7.41 - 7.38 (m, 2H), 7.34 - 7.31 (m, 1H), 7.20 (d, 1H), 5.26 (s, 2H).

step f : 1-( Benzyloxy )-3-( Difluoromethyl )-2- iodine -5-( Trifluoromethyl ) benzene

To a mixture of 3-(benzyloxy)-2-iodo-5-(trifluoromethyl)benzaldehyde (1500.0 mg, 3.69 mmol, 1.0 eq) in DCM (30 mL) was added ethylamino group at 0 °C Sulfur trifluoride (893.04 mg, 5.54 mmol, 1.5 eq), and the mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched by 20 mL ice water, then extracted with EtOAc (30 mL × 3), washed with brine (20 mL × 2), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was decompressed Concentrate to give a white solid. The solid was purified by column (PE:EA = 20:1 to 10:1) to give 1-(benzyloxy)-3-(difluoromethyl)-2-iodo-5- (Trifluoromethyl)benzene (1300 mg, 82% yield). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.54 (d, 2H), 7.44 - 7.38 (m, 4H), 7.36 - 7.32 (m, 1H), 7.00 (t, 1H), 5.31 (s, 2H)

step G : 2-(2-( Benzyloxy )-6-( Difluoromethyl )-4-( Trifluoromethyl ) Phenyl )-4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane

1-(Benzyloxy)-3-(difluoromethyl)-2- _iodo -5-(trifluoromethyl)benzene (400.0 mg, 0.93 mmol, 1.0 eq) and n BuLi ( 0.56 mL, 1.4 mmol, 1.5 eq) to a mixture in THF (5 mL) was added dropwise 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaborane (312.9 mg, 1.68 mmol, 1.8 eq), and the mixture was stirred at -60°C for 30 minutes. The mixture was poured into NH ₄ Cl solution (15 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column (PE:EA=20:1 to 10:1) to give 2-(2-(benzyloxy)-6-(difluoromethyl)-4-( Trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50.0 mg, 13% yield). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.51 (s, 1H), 7.50 (s, 1H), 7.41 - 7.32 (m, 5H), 5.16 (s, 2H), 1.26 (s, 12H).

step h : 5- bromine -N-[(3 R )-1- methyl -3- piperidinyl ] zozolo [4,5-b] pyridine -2- amine

(3R)-1-Methylpiperidin-3-amine dihydrochloride (172.0 mg, 0.92 mmol, 1.12 eq, CAS: 1157849-50-7) and triethylamine (0.4 mL, 2.87 mmol, 3.48 eq ) to 5-bromo-2-methylsulfanyl-oxazolo[4,5-b]pyridine (202.0 mg, 0.82 mmol, 1.0 eq) in 1,4-dioxane (4 mL) The solution was stirred, and the reaction mixture was heated to 90 °C. The reaction was stirred for 3 days. Add triethylamine (0.3 mL, 2.15 mmol, 2.6 eq) and (3R)-1-ethylpiperidin-3-amine dihydrochloride (164.0 mg, 0.82 mmol, 1.0 eq), and react at 90°C Stir for 2 hours. Additional (3R)-1-ethylpiperidin-3-amine dihydrochloride (42.0 mg, 0.21 mmol, 0.25 eq) and triethylamine (0.15 mL, 1.08 mmol, 1.3 eq) were then added, and the reaction Stir at 90°C for 18 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude reaction mixture was purified by silica gel chromatography (40 g, 0% to 20% MeOH (containing 0.7M NH ₃ )/EtOAc) to afford the title compound (222.0 mg, 84% yield) as a light brown solid. LC-MS: m/z 311.1/313.1 [M+H] ⁺ , ESI pos.

step I : (R)-5-(2-( Benzyloxy )-6-( Difluoromethyl )-4-( Trifluoromethyl ) Phenyl )-N-(1- Methylpiperidine -3- base ) zozolo [4,5-b] pyridine -2- amine

To 2-(2-(benzyloxy)-6-(difluoromethyl)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2 -Dioxaborolane (100 mg, 0.23 mmol, 1.0 eq) and 5-bromo-N-[(3R)-1-methyl-3-piperidinyl]oxazolo[4,5- b ]pyridin-2-amine ( Example 30 , Step H ) (87.2 mg, 0.28 mmol, 1.2 eq) To a solution in a mixture of 1,4-dioxane (5 mL) and water (1 mL) was added K ₂ CO ₃ (74.26 mg, 0.7 mmol, 3.0 eq) and Pd(dppf) ₂ Cl ₂ (6.74 mg, 0.02 mmol, 0.1 eq), and the mixture was stirred at 90° C. under N ₂ for 2 hours. The reaction mixture was concentrated under reduced pressure to remove solvent to give a brown solid. The solid was purified by reverse phase flash chromatography (0.1% TFA water/ACN conditions). The eluate was dried by lyophilization to give the title compound (20.0 mg, 16% yield) as a white solid. LC-MS: m/z 533.2 [M+H] ⁺ , ESI pos.

step I : ( R )-3-( Difluoromethyl )-2-(2-((1- Methylpiperidine -3- base ) Amino ) zozolo [4,5-b] pyridine -5- base )-5-( Trifluoromethyl ) phenol

To ( R )-5-(2-(benzyloxy)-6-(difluoromethyl)-4-(trifluoromethyl)phenyl) -N- (1-methylpiperidin-3-yl ) To a mixture of oxazolo[4,5-b]pyridin-2-amine (10.0 mg, 0.02 mmol, 1.0 eq) in EtOAc (1 mL) was added Pd/C (20.0 mg), and the mixture was dissolved at 25 °C and stirred for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a white solid. The solid was purified by reverse phase flash chromatography (0.1% TFA water/ACN conditions). The eluate was dried by lyophilization to afford the title compound (4.47 mg, 42% yield) as a white solid. LC-MS: m/z 443.2 [M+H] ⁺ , ESI pos. Example 31 : 2-[2-[[(3R)-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridin -5- yl ]-3- methoxy -5-( Trifluoromethyl ) phenol; 2,2,2- Trifluoroacetate

step A : 3- Amino -5-( Trifluoromethyl ) phenol

A solution of 3-nitro-5-(trifluoromethyl)phenol (8000.0 mg, 38.63 mmol, 1.0 eq) in methanol (80 mL) was evacuated and backfilled three times with nitrogen, then Pd/C (200 mg, 10% purity), and the mixture was evacuated and backfilled three times with hydrogen. The reaction mixture was stirred at 25 °C for 3 hours under hydrogen gas (15 psi). The reaction mixture was filtered and the solid was washed with MeOH (50 mL x 3), the filtrate was concentrated under reduced pressure to give 3-amino-5-(trifluoromethyl)phenol (6400 mg, yield rate of 94%). LC-MS: m/z 178.0 [M+H] ⁺ , ESI pos.

step B : 5-( Trifluoromethyl ) benzene -1,3- diol

A solution of 3-amino-5-(trifluoromethyl)phenol (2000.0 mg, 11.29 mmol, 1.0 eq) in concentrated sulfuric acid (8.0 mL, 150.1 mmol, 13.29 eq) and water (7 mL) was cooled to 0 °C, then a solution of NaNO ₂ (1168.53 mg, 16.94 mmol, 1.5 eq) in water (4 mL) was added dropwise and after stirring for 15 min, the excess was destroyed by adding urea (339.07 mg, 5.65 mmol, 0.5 eq). Nitrous acid, then this cooled solution was added dropwise to a refluxing saturated solution of copper sulfate (25.0 g, 156.64 mmol, 13.87 eq) in water (100 mL) and stirred at this temperature for 30 minutes. After cooling to ambient temperature, the reaction mixture was extracted with EA (100 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to C18 column chromatography (0.1% NH ₄ OH in water/MeCN), and the desired fractions were extracted with EA (100 mL × 3), washed with brine (20 mL), and combined The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 5-(trifluoromethyl)benzene-1,3-diol (1.20 g, 60% yield) as a red oil. LC-MS: m/z 354.9 [2M-H] ^- , ESI neg.

step C : 2- iodine -5-( Trifluoromethyl ) benzene -1,3- diol

To a solution of 5-(trifluoromethyl)benzene-1,3-diol (1200 mg, 6.74 mmol, 1.0 eq) in THF (70 mL) and water (70 mL) was added iodine dropwise at 0 °C (1710.02 mg, 6.74 mmol, 1.0 eq) in THF (10 mL), then sodium bicarbonate (566.01 mg, 6.74 mmol, 1.0 eq) was added. After stirring at 0°C for 10 minutes, the reaction mixture was warmed to 25°C and stirred at this temperature for a further 50 minutes. The reaction mixture was quenched with saturated aqueous sodium sulfite (100 mL), extracted with EA (100 mL × 3), washed with brine (30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE to PE: EA = 10:1) to obtain 2-iodo-5-(trifluoromethyl)benzene-1,3-diol as a yellow solid ( 1000 mg, yield 49%). LC-MS: m/z 302.8, [MH] ^- , ESI neg.

step D. : 3-( Benzyloxy )-2- iodine -5-( Trifluoromethyl ) phenol

To a solution of 2-iodo-5-(trifluoromethyl)benzene-1,3-diol (200 mg, 0.66 mmol, 1.0 eq) in DMF (3 mL) was added potassium carbonate (136.38 mg , 0.99 mmol, 1.5 eq) and BnBr (112.52 mg, 0.66 mmol, 1.0 eq), then the reaction mixture was stirred at this temperature under nitrogen gas for 2 hours. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (30 mL), extracted with EA (100 mL × 2), washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure . The residue was purified by prep-TLC (PE: EA = 15:1) to give 3-(benzyloxy)-2-iodo-5-(trifluoromethyl)phenol (110.0 mg, yielding rate 42%). LC-MS: m/z 392.9, [MH] ^- , ESI neg.

step E. : 1-( Benzyloxy )-2- iodine -3- Methoxy -5-( Trifluoromethyl ) benzene

To a solution of 3-(benzyloxy)-2-iodo-5-(trifluoromethyl)phenol (330.0 mg, 0.84 mmol, 1.0 eq) in DMF (6 mL) was added potassium carbonate (47.98 mg, 1.26 mmol, 1.5 eq), then _CH3I (237.69 mg, 1.67 mmol, 2.0 eq) was added dropwise, and the reaction mixture was stirred at 25 °C under nitrogen atmosphere for 1 h. The reaction mixture was quenched with 25 °C saturated aqueous _NH4Cl (50 mL) added dropwise, extracted with EA (200 mL x 3), washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and The filtrate was concentrated under reduced pressure to give 1-(benzyloxy)-2-iodo-3-methoxy-5-(trifluoromethyl)benzene (400.0 mg, 88% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54 - 7.52 (m, 2H), 7.44 - 7.33 (m, 4H), 6.79 (s, 1H), 6.74 (s, 1H), 5.21 (s, 2H), 3.96 (s, 3H).

step f : 2-(2-( Benzyloxy )-6- Methoxy -4-( Trifluoromethyl ) Phenyl )-4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane

1-(Benzyloxy)-2-iodo-3-methoxy-5-(trifluoromethyl)benzene (200.0 mg, 0.49 mmol, 1.0 eq) and 2-isopropoxy- To a solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (266.47 mg, 1.43 mmol, 2.0 eq) in THF (3 mL) was added dropwise n- BuLi (0.43 mL, 1.07 mmol, 1.5 eq), then the reaction mixture was stirred at this temperature under nitrogen atmosphere for 1 h. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (30 mL), extracted with EA (100 mL × 3), washed with brine (20 mL), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was dissolved in Concentrate under reduced pressure. The residue was purified by prep-TLC (PE:EA = 20:1) to give the title compound (50.0 mg) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 - 7.43 (m, 2H), 7.36 - 7.31 (m, 3H), 6.79 (s, 1H), 6.72 (s, 1H), 5.07 (s, 2H), 3.83 (s, 3H), 1.31 (s, 12H).

step G : 3- Methoxy -2-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base )-5-( Trifluoromethyl ) phenol

2-(2-(Benzyloxy)-6-methoxy-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxo A solution of borane (30.0 mg, 0.06 mmol, 1.0 eq) in ethyl acetate (4 mL) and methanol (1 mL) was evacuated and backfilled three times with nitrogen, then Pd/C (15.0 mg, purity 10 %). The reaction was evacuated and backfilled three times with hydrogen, then the reaction mixture was stirred at 25 °C for 0.5 h under hydrogen gas (1100 mmHg). The reaction mixture was filtered, and the solid was washed with MeOH (20 mL × 2), and the filtrate was concentrated under reduced pressure to give 3-methoxy-2-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (22.0 mg, 92% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.79 (s, 1H), 6.77 (s, 1H), 6.57 (s, 1H), 3.86 (s, 3H), 1.39 (s, 12H).

step h : 2-[2-[[(3R)-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- Methoxy -5-( Trifluoromethyl ) phenol ; 2,2,2- Trifluoroacetate

To ( R )-5-bromo- N- (1-ethylpiperidin-3-yl)oxazolo[4,5-b]pyridin-2-amine; 2,2,2-trifluoroacetic acid (20.0 mg, 0.05 mmol, 1.0 eq), 3-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5 -(Trifluoromethyl)phenol (18.83 mg, 0.06 mmol, 1.3 eq) and potassium carbonate (31.42 mg, 0.23 mmol, 5.0 eq) in 1,4-dioxane (2 mL) and water (0.2 mL) To the solution of Pd(dppf)Cl ₂ (3.33 mg, 0.0 mmol, 0.1 eq) was added. The reaction mixture was then evacuated and backfilled with nitrogen three times, and then the reaction mixture was stirred at 100° C. for 3 hours under nitrogen atmosphere. After cooling to ambient temperature, the reaction mixture was directly passed through a C18 column chromatography (0.1% TFA condition in water/MeCN) and then preparative HPLC (instrument ACSWH-GX-N, method: column Phenomenex Synergi Polar-RP 100 × 25 mm × 4 um, condition: water (TFA)-ACN, B at start: 31, B at end: 51. Gradient time (min): 7, 100% B hold time (min): 2 , flow rate (mL/min): 25) was purified to give (R)-2-(2-((1-ethylpiperidin-3-yl)amino)oxazolo[4,5- b] pyridin-5-yl)-3-methoxy-5-(trifluoromethyl)phenol as TFA salt (6.57 mg, 26% yield). LC-MS: m/z 437.1 [M+H] ⁺ , ESI pos. Example 32 : ( racemic )-2-[2-[(1- ethyl -3- piperidinyl ) amino ] oxazolo [4,5-b] pyrazin -5- yl ]-3- Methyl -5-( trifluoromethyl ) phenol; 2,2,2- trifluoroacetate

step A : 5-( Trifluoromethyl )-1,2,4- three 𠯤 -3- amine

To a stirred solution of benzyl alcohol (5.19 g, 47.98 mmol, 1.0 eq) in tetrahydrofuran (100 mL) was added NaH (1.92 g, 47.98 mmol, 1.0 eq) at 20 °C. The mixture was stirred at ambient temperature for 10 minutes. Then 3-bromo-6-chloro-pyrazin-2-amine, CAS: 212779-21-0 (10.0 g, 47.98 mmol, 1.0 eq) was added and the reaction mixture was heated at 70 °C for 4 hours. The mixture was quenched with 5 mL of water, ethyl acetate (50 mL) and water (20 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined extracts were washed with brine (60 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give a residue, which was chromatographed on silica gel (with petroleum ether:ethyl acetate=10 :1 to 3:1 eluting) to afford 3-benzyloxy-6-chloro-pyrazin-2-amine (3.0 g, 25% yield) as a yellow solid. LC-MS: m/z 236.0 [M+H] ⁺ , ESI pos.

step B : 2-(6- Amino -5- Benzyloxy - pyrazine -2- base )-3- methyl -5-( Trifluoromethyl ) phenol

The device was dried by heating with an air heater under vacuum. To 3-benzyloxy-6-chloro-pyrazin-2-amine (1.3 g, 5.52 mmol, 1.0 eq), CsF (2.51 g, 16.55 mmol, 3.0 eq) and 3-methyl-2- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (2.5 g, 8.27 mmol, 1.5 eq ) to a mixture of 1,4-dioxane (30 mL) and water (5 mL) was added XPhos Pd G ₃ (0.47 g, 0.55 mmol, 0.1 eq), and the mixture was stirred at 100°C under N ₂ 16 hours to obtain a brown solution. Cooled to 25 °C, the mixture was quenched by 10 mL of water, ethyl acetate (50 mL) and water (20 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined extracts were washed with brine (60 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give a residue, which was chromatographed on silica gel (with petroleum ether:ethyl acetate=10 :1 to 3:1 elution) to obtain 2-(6-amino-5-benzyloxy-pyrazin-2-yl)-3-methyl-5-(trifluoromethyl ) phenol (1.5 g, 60% yield). LC-MS: m/z 376.2 [M+H] ⁺ , ESI pos.

step C : 3- Isothiocyanatopiperidine -1- formic acid ( Racemization )- Benzyl ester

TEA (862.2 mg, 8.54 mmol, 2.0 eq), benzyl 3-aminopiperidine-1-carboxylate, CAS: 711002-74-3 (1.0 g, 4.27 mmol, 1.0 eq) in dichloromethane at 0°C (5 mL) To the stirred solution was added thiophosgene solution (490.76 mg, 4.27 mmol, 1.0 eq) dropwise. After stirring at 25°C for 2 hours, the mixture was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (eluting with petroleum ether: ethyl acetate = 10:1 to 3:1) to give benzyl 3-isothiocyanatopiperidine-1-carboxylate (1.0 g, yield 85%). ¹ H NMR (400 MHz, DMSO-d6) δ 7.43 - 7.28 (m, 5H), 5.19 - 5.04 (m, 2H), 4.06 - 4.00 (m, 1H), 3.94 - 3.66 (m, 2H), 3.40 - 3.38 (m, 1H), 3.20-3.04 (m, 1H), 1.94 - 1.83 (m, 2H), 1.68 - 1.49 (m, 2H).

step D. : ( Racemization )-3-( Benzyloxy )-6-(2- methyl -4-( Trifluoromethyl )-6-((2-( Trimethylsilyl ) Ethoxy )- Methoxy ) Phenyl ) pyrazine -2- amine

The device was dried by heating with an air heater under vacuum. cesium carbonate (390.63 mg, 1.2 mmol, 1.5 eq) and 2-(6-amino-5-benzyloxy-pyrazin-2-yl)-3-methyl-5-(trifluoromethane In a mixture of phenol (300.0 mg, 0.8 mmol, 1.0 eq) in DMF (5 mL), the mixture was stirred at 25°C for 30 minutes, then SEMCl (199.8 mg, 1.2 mmol, 1.5 eq) was added, and Stir at 25°C for 2 hours. The mixture was partitioned between ethyl acetate (50 mL) and water (20 mL). The organic portion was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluted with petroleum ether: ethyl acetate = 10:1 to 3:1) to give the title compound (200 mg, yield 50%) as a colorless oil. LC-MS: m/z 506.2 [M+H] ⁺ , ESI pos.

step E. : 3-[[3- Benzyloxy -6-[2- methyl -4-( Trifluoromethyl )-6-(2- Trimethylsilylethoxy - Methoxy ) Phenyl ] pyrazine -2- base ] Thiocarbamate amino group ] piperidine -1- formic acid ( Racemization )- Benzyl ester

To 3-benzyloxy-6-[2-methyl-4-(trifluoromethyl)-6-(2-trimethylsilylethoxymethoxy)phenyl]pyrazin-2-amine (150.0 mg, 0.3 mmol, 1.0 eq) to a stirred solution in THF (1.5 mL) was added NaH (23.73 mg, 0.59 mmol, 60%, 2.0 eq), stirred at 25 °C for 0.5 h, then 3-isosulfur Benzyl cyanopiperidine-1-carboxylate (98.38 mg, 0.36 mmol, 1.2 eq) and stirred at 25°C for 3 hours. The mixture was quenched by 5 mL of water. The aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over _{anhydrous Na2SO4} , filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (eluted with petroleum ether: ethyl acetate = 10:1 to 3:1) to give the title compound (60.0 mg, yield 26%) as a yellow solid. LC-MS: m/z 782.5 [M+H] ⁺ , ESI pos.

step f : ( Racemization )-1-(3- hydroxyl -6-(2- hydroxyl -6- methyl -4-( Trifluoromethyl ) Phenyl ) pyrazine -2- base )-3-( piperidine -3- base ) Thiourea; Trifluoroacetate

3-[[3-benzyloxy-6-[2-methyl-4-(trifluoromethyl)-6-(2-trimethylsilylethoxymethoxy)phenyl]pyrazine -2-yl]carbamatethioamino]piperidine-1-carboxylate (50.0 mg, 0.06 mmol, 1.0 eq), anisole (0.07 mL, 0.64 mmol, 10.0 eq) and TFA (1.0 mL) Stir at 75°C for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18 column chromatography (20 g, 0.1% TFA in water/MeCN) and the eluate was lyophilized to give 1-[3-hydroxy-6-[2 as a yellow solid -Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyrazin-2-yl]-3-(3-piperidinyl)thiourea; TFA salt (30.0 mg, 99% yield) . LC-MS: m/z 428.2 [M+H] ⁺ (ESI pos).

step G : ( Racemization )-1-(1- Ethyl -3- piperidinyl )-3-[3- hydroxyl -6-[2- hydroxyl -6- methyl -4-( Trifluoromethyl ) Phenyl ] pyrazine -2- base ] Thiourea; Trifluoroacetate

To 1-[3-hydroxy-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyrazin-2-yl]-3-(3-piperidinyl)thiourea ; TFA salt (25.0 mg, 0.05 mmol, 1.0 eq), acetic acid (3.33 mg, 0.06 mmol, 1.2 eq) in methanol (1 mL) was added acetaldehyde (0.03 mL, 0.23 mmol, 40%, 5.0 eq ) and stirred at 25°C for 0.5 hours, then added NaBH ₃ CN (14.51 mg, 0.23 mmol, 5.0 eq) and stirred at 25°C for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18 column chromatography (20 g, 0.1% TFA in water/MeCN) and the eluate was lyophilized to give 1-(1-ethyl-3-piperene as a yellow solid Pyridyl)-3-[3-hydroxy-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyrazin-2-yl]thiourea; TFA salt (25.0 mg, Yield 94%). LC-MS: m/z 456.3 [M+H] ⁺ , ESI pos.

step h : ( Racemization )-2-[2-[(1- Ethyl -3- piperidinyl ) Amino ] zozolo [4,5-b] pyrazine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol; 2,2,2- Trifluoroacetate

To 1-(1-ethyl-3-piperidinyl)-3-[3-hydroxyl-6-[2-hydroxyl-6-methyl-4-(trifluoromethyl)phenyl]pyrazine-2 -yl]thiourea (TFA salt) (15.0 mg, 0.03 mmol, 1.0 eq), tetrabutylammonium iodide (9.73 mg, 0.03 mmol, 1.0 eq) in tetrahydrofuran (0.5 mL) was added hydrogen peroxide (5.97 mg, 0.05 mmol, 2.0 eq) and stirred at 25°C for 2 hours, then the reaction mixture was concentrated under reduced pressure. The residue was purified by C18 column chromatography (20 g, 0.1% TFA in water/MeCN) and the eluate was lyophilized to give the title compound (10.2 mg, 70% yield) as a yellow solid . LC-MS: m/z 422.2 [M+H] ⁺ , ESI pos. Example 33 : 3- methyl -2-[7- methyl -2-[[(3 R )-1- methyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridine -5- yl ]-5-( trifluoromethyl ) phenol; 2,2,2- trifluoroacetate

step A : 6- chlorine -4- methyl -2- Nitropyridine -3- alcohol

The device was dried by heating with an air heater under vacuum. In a three-neck round bottom flask, 6-chloro-4-methyl-pyridin-3-ol (CAS: 1227502-89-7) (800 mg, 5.57 mmol, 1.0 eq) was added to H ₂ SO at 0 °C ₄ (5.46 g, 55.72 mmol, 10.0 eq), then a mixture of fuming nitric acid (657.0 mg, 10.43 mmol, 1.87 eq) and H ₂ SO ₄ (1.09 g, 11.14 mmol, 2.0 eq) was added to the mixture, And the mixture was stirred at 0°C for 1 hour, then the mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched by 20 mL of ice water, then extracted by EtOAc (30 ml × 3), washed with brine (20 ml × 2), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure . The residue was purified by silica gel column chromatography (PE:EA = 20:1 to 10:1) to give the desired product as 6-chloro-4-methyl-2-nitropyridine- 3-ol (1200.0 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.95 (brs, 1H), 7.77 (s, 1H), 2.32 (s, 3H).

step B : 2- Amino -6- chlorine -4- picoline -3- alcohol

Fe ( 1.48 g, 26.52 mmol, 10.0 eq) and NH ₄ Cl (1.42 g, 26.52 mmol, 10.0 eq), then the reaction mixture was stirred at 70°C under nitrogen atmosphere for 2 hours. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc:THF = 10:1:1) to give the title compound (150.0 mg, yield 36%) as a yellow solid. LC-MS: m/z 159.0 [M+H] ⁺ , ESI pos.

step C : 5- chlorine -7- Methyloxazolo [4,5- b ] pyridine -2- Thiol

To a solution of 2-amino-6-chloro-4-methylpyridin-3-ol (150.0 mg, 0.95 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL) in batches Bis(1H-imidazol-1-yl)methanethione (303.4 mg, 1.7 mmol, 1.8 eq) was added and the reaction mixture was stirred at 20°C under nitrogen atmosphere for 12 hours. The reaction was quenched with 20 mL of water, extracted with EtOAc (100 mL × 2), washed with 1N aqueous HCl (20 mL × 2), brine (20 mL), dried over Na ₂ SO ₄ , filtered, and the filtrate was dissolved in Concentration under reduced pressure gave 5-chloro-7-methyloxazolo[4,5- b ]pyridine-2-thiol (180.0 mg, 71% yield) as a yellow solid, which was obtained without further purification. for the next step. LC-MS: m/z 200.9, [M+H] ⁺ , ESI pos.

step D. : 2,5- Dichloro -7- Methyloxazolo [4,5-b] pyridine

To 5-chloro-7-methyloxazolo[4,5-b]pyridine-2-thiol (150.0 mg, 0.75 mmol, 1.0 eq) in oxalyl chloride (4.74 g, 37.38 mmol, 50.0 eq) To the mixture was added DMF (5.46 mg, 0.07 mmol, 0.1 eq), and the mixture was stirred at 50°C for 1 hour. The reaction mixture was concentrated under vacuum. The residue was added to ice water (20 mL) at 0°C, and extracted with EtOAc (30 mL×2). The combined extracts were washed with brine (60 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (Hexane/EtOAc, 5:1) to give the title compound (40.0 mg, 26% yield) as a white solid. LC-MS: m/z 203.0, [M+H] ⁺ , ESI pos.

step E. : ( R )-5- chlorine -7- methyl - N -(1- Methylpiperidine -3- base ) zozolo [4,5- b ] pyridine -2- amine

To a solution of 2,5-dichloro-7-methyloxazolo[4,5- b ]pyridine (40.0 mg, 0.2 mmol, 1.0 eq) in NMP (2 mL) was added ( R )-1- Methylpiperidin-3-amine (67.49 mg, 0.6 mmol, 3.0 eq) and DIEA (127.07 mg, 0.99 mmol, 5.0 eq). The mixture was stirred at 20 °C for 2 hours. The mixture was purified by C18 column chromatography (0.1% TFA in water/MeCN conditions). The eluate was lyophilized to give the desired product ( R )-5-chloro-7-methyl- N- (1-methylpiperidin-3-yl)oxazolo[4,5- b] Pyridin-2-amine (60.0 mg, 77% yield, TFA salt). LC-MS: m/z 281.1, [M+H] ⁺ , ESI pos.

step f : 3- methyl -2-[7- methyl -2-[[(3R)-1- methyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-5-( Trifluoromethyl ) phenol; 2,2,2- Trifluoroacetate

Under nitrogen gas, 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoro Methyl)phenol (36.73 mg, 0.12 mmol, 1.2 eq) and ( R )-5-chloro-7-methyl-N-(1-methylpiperidin-3-yl) oxazolo[4,5- b] To a solution of pyridin-2-amine (40.0 mg, 0.1 mmol, 1.0 eq) in 1,4-dioxane (1.5 mL) and water (0.3 mL) was added CsF (61.56 mg, 0.41 mmol, 4.0 eq ) and Xphos Pd G3 (17.17 mg, 0.02 mmol, 0.2 eq). The mixture was stirred at 100 °C for 3 hours. The mixture was concentrated in vacuo, and the residue was analyzed by preparative HPLC (method: column: Phenomenex Synergi Polar-RP 100 × 25 mm × 4 μm; condition: water (TFA)-MeCN, start B: 27; end Time B: 47; Gradient time (min): 7; 100% B hold time (min): 2; Flow rate (mL/min): 25) Purification. The eluate was lyophilized to give the title compound (19.4 mg, 34% yield, TFA salt) as a yellow solid. LC-MS: m/z 421.1, [M+H] ⁺ (ESI pos). Example 34 : 5- methoxy -3- methyl -2-[2-[[(3 R )-1- methyl -3- piperidinyl ] amino ] oxazolo [4,5- b ] Pyridin -5- yl ] phenol

step A : 2- iodine -5- Methoxy -3- methyl - phenol

To a stirred solution of 3-methoxy-5-methylphenol (1.0 g, 7.24 mmol, 1.0 eq) (CAS: 3209-13-0) in toluene (42 mL) at room temperature was added in oil 60% sodium hydride (614.0 mg, 15.35 mmol, 2.12 eq) and the reaction was stirred for 1 hour. Then, iodine (1.86 g, 7.33 mmol, 1.01 eq) was added and the reaction was stirred for 4 hours. The reaction mixture was carefully poured into a mixture of ice-cold water (90 mL) and 1M HCl (10 mL) and stirred for 10 min. The resulting solution was diluted with water (50 mL) and DCM (50 mL). The separated aqueous layer was further extracted with DCM (2 x 50 mL), and the combined organic layers were dried (Na2SO4), filtered and concentrated. The crude reaction mixture was purified by silica gel column chromatography (40 g, 25% to 100% DCM:isohexane) to afford the title compound (779.0 mg, 40% yield) as a white crystalline solid. LC-MS m/z 264.9 [M+H] ⁺ , ESI pos.

step B : 1- Benzyloxy -2- iodine -5- Methoxy -3- methyl - benzene

A suspension of potassium carbonate (833.0 mg, 6.03 mmol, 3.0 eq) in acetone (30 mL) was sonicated for 5 minutes, then 2-iodo-5-methoxy-3-methyl-phenol (530.0 mg, 2.01 mmol, 1.0 eq), and the mixture was further sonicated for 5 minutes before bromotoluene (265.0 uL, 2.23 mmol, 1.11 eq) was added. The resulting stirred mixture was heated to reflux for 2.5 hours, then cooled to room temperature and concentrated. The residue was dissolved in DCM (50 mL) and washed with 50 vol% brine (100 mL). The aqueous layer was re-extracted with DCM (2 x 50 mL), and the combined organic layers were dried (MgSO4), filtered and concentrated. The crude product was purified by silica gel column chromatography (40 g, 0% to 50% DCM:isohexane) to give the title compound (628.0 mg, 86% yield) as a colorless oil. LC-MS m/z 355.2 [M+H] ⁺ , ESI pos.

step C : 2-(2- Benzyloxy -4- Methoxy -6- methyl - Phenyl )-4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane

Add 1-benzyloxy-2-iodo-5-methoxy-3-methyl-benzene (256.0 mg, 0.72 mmol, 1.0 eq) and 2-isopropoxy-4,4,5 at -78°C ,5-Tetramethyl-1,3,2-dioxaborolane (165.0 µL, 0.81 mmol, 1.12 eq) was added to a stirred solution of n -BuLi (2.5 M in hexane, 350 µL, 0.88 mmol, 1.21 eq), and the reaction was stirred for 2 hours. Add additional n -BuLi (2.5 M in hexane, 350.0 µL, 0.88 mmol, 1.21 eq) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2- Dioxaborolane (165.0 uL, 0.81 mmol, 1.12 eq) and the reaction was stirred for 30 minutes. The reaction mixture was warmed to about 0 °C and quenched with saturated NH4Cl (5 mL), then diluted with water (45 mL) and DCM (50 mL) and separated. The separated aqueous layer was further extracted with DCM (2 x 50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel column chromatography (40 g, 0% to 20% MTBE:isohexane) to give the title compound (133 mg, 50% yield) as a colorless oil. LC-MS m/z 355.6 [M+H] ⁺ , ESI pos.

step D. : 5-(2- Benzyloxy -4- Methoxy -6- methyl - Phenyl )- N -[(3R)-1- methyl -3- piperidinyl ] zozolo -[4,5- b ] pyridine -2- amine

2-(2-Benzyloxy-4-methoxy-6-methyl-phenyl)-4,4,5 in 1,4-dioxane (4 mL) and water (1 mL), 5-tetramethyl-1,3,2-dioxaborolane (67.0 mg, 0.19 mmol, 0.84 eq), 5-bromo-N-[(3R)-1-methyl-3-piperidine Base] oxazolo[4,5-b]pyridin-2-amine ( Example 30 , Step H ) (70.0 mg, 0.22 mmol, 1.0 eq) and potassium carbonate (61.0 mg, 0.44 mmol, 1.96 eq) bubbled ( While sonicating, sparge with nitrogen for 10 min). Xphos Pd G3 (9.0 mg, 0.01 mmol, 0.05 eq) and XPhos (3.0 mg, 0.01 mmol, 0.03 eq) were added and the reaction mixture was stirred at 90 °C for 4 hours. The reaction was cooled to room temperature and additional Xphos Pd G3 (10.0 mg, 0.01 mmol, 0.05 eq), XPhos (3.0 mg, 0.01 mmol, 0.03 eq) and potassium carbonate (58.0 mg, 0.42 mmol, 1.87 eq) were added, And the reaction mixture was stirred at 90 °C for 16 hours. The reaction was cooled and degassed, then 2-(2-benzyloxy-4-methoxy-6-methyl-phenyl)-4,4 in 1,4-dioxane (0.5 mL) was added ,5,5-tetramethyl-1,3,2-dioxaborolane (66.0 mg, 0.19 mmol, 0.83 eq), then add Xphos Pd G3 (5.0 mg, 0.01 mmol, 0.03 eq) and XPhos (2.0 mg, 0.0 mmol, 0.02 eq), and the reaction was stirred at 90°C for 2 hours. The reaction mixture was cooled to room temperature, concentrated, and the crude product was purified by silica gel chromatography (40 g, 0% to 20% MeOH (0.7 M NH 3 ): EtOAc) followed by reverse phase column chromatography (C18 , 43 g, 10% to 60% acetonitrile (0.1% formic acid):water (0.1% formic acid)) were purified to afford the title compound (18.0 mg, 17% yield) as a brown solid. LC-MS m/z 459.4 [M+H] ⁺ , ESI pos.

step E. : 5- Methoxy -3- methyl -2-[2-[[(3R)-1- methyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ] phenol

5-(2-Benzyloxy-4-methoxy-6-methyl-phenyl)-N-[(3R)-1-methyl-3-piperidinyl]oxazolo[4,5 -b] A stirred solution of pyridin-2-amine (17.0 mg, 0.04 mmol, 1.0 eq) and Pd/C (type 87) (6.0 mg, 0.0 mmol, 0.08 eq) in EtOAc (4 mL) was placed at 1 bar in a hydrogenation vessel under H2. The reaction was stirred at room temperature for 32 hours. The reaction mixture was diluted with EtOH (1 mL) and additional Pd/C (Type 87) (6.0 mg, 0.0 mmol, 0.08 eq) was added and the reaction was placed in the hydrogenation vessel under 1 bar H2 for an additional 19 Hour. The reaction mixture was filtered through celite, the filter cake was rinsed with EtOH (50 mL) and concentrated to give the title compound (6.1 mg, 39% yield) as a light brown solid. LC-MS m/z 369.3 [M+H] ⁺ , ESI pos. Example 35 : 5-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ]-6- methyl - oxazolo [4,5- b ] pyridin -5- yl ]-2,3- Dihydrobenzofuran -4- ol

step A : 6- bromine -5- chlorine -3H- zozolo [4,5- b ] pyridine -2- Thione

To commercially available 2-amino-5-bromo-6-chloro-pyridin-3-ol (CAS # 1131041-72-9, 1.06 g, 4.74 mmol, 1.00 eq) under argon atmosphere in N, To a solution in N -dimethylformamide (13.7 mL) was added 1,1'-thiocarbonyldiimidazole (972.2 mg, 5.46 mmol, 1.15 eq). The reaction mixture was stirred overnight at room temperature. Then, potassium carbonate (1.31 g, 9.49 mmol, 2.00 eq) and methyl iodide (343 µL, 5.48 mmol, 1.16 eq) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours to complete the reaction. The reaction mixture was cooled to 0°C and about 30 mL of water was added dropwise (precipitation formed) and further stirred at 0°C for 30 minutes. The suspension was filtered and rinsed with water to give the desired product (850 mg, 61% yield) as a light brown solid. LC-MS: m/z 280.9 [M+H] ⁺ , ESI pos.

step B : 6- bromine -5- chlorine - N -[(3 R )-1- Ethyl -3- piperidinyl ] zozolo [4,5- b ] pyridine -2- amine

To the above 6-bromo-5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 850 mg, 2.89 mmol, 1.00 eq) at 1,4 - Add [(3 R )-1-ethyl-3-piperidinyl]amine (411.1 mg, 457.8 µL, 3.21 mmol, 1.11 eq) and triethylamine ( 327.4 mg, 450.9 µL, 3.24 mmol, 1.12 eq). The orange solution was stirred overnight at 90°C. LC-MS indicated the reaction was complete. The reaction mixture was cooled to room temperature and extracted with about 40 mL of ethyl acetate and about 5 mL of saturated NaHCO ₃ solution. The aqueous layer was back extracted with about 40 mL of ethyl acetate. The organic layer was washed with about 5 mL of water and about 5 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was subjected to flash chromatography (silica gel, 25 g, DCM, MeOH 0% to 20% MeOH) to afford the title compound (691 mg, 63% yield) as a light brown solid. LC-MS: m/z 359.1 [M+H] ⁺ , ESI pos.

step C : 5- chlorine - N -[(3 R )-1- Ethyl -3- piperidinyl ]-6- methyl - zozolo [4,5-b] pyridine -2- amine

Under argon, to the above (6-bromo-5-chloro- N -[(3R)-1-ethyl-3-piperidinyl]oxazolo[4,5- b ]pyridin-2-amine ( 698 mg, 1.94 mmol, 1.00 eq) to a solution in N,N -dimethylformamide (11.7 mL) was added commercially available tributyl(methyl)stannane (CAS # 1528-01- 4, 769.7 mg, 706.2 µL, 2.52 mmol, 1.30 eq), PdCl ₂ (PPh ₃ ) (136.2 mg, 0.194 mmol, 0.100 eq). The reaction was stirred at 100 °C for one hour. LC-MS showed only starting material, Therefore additional _PdCl2 ( _PPh3 ) (136.0 mg, 0.194 mmol, 0.10 eq) was added to the reaction mixture. The mixture was stirred at 100 °C for four hours until the reaction was complete. The reaction mixture was filtered through celite and washed with DCM. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, DCM/MeOH 0% to 20% MeOH). The product and the corresponding debrominated product could not be separated. All components containing the product Fractions were combined and concentrated in vacuo to give a brown solid (460 mg).LC-MS: m/z 281.1 [M+H] ⁺ , ESI pos.

step D. : 5- bromine -2,3- Dihydrobenzofuran -4- alcohol

To a solution of dihydrobenzofuran-4-ol (5.0 g, 36.7 mmol, 1.0 eq) in methanol (100 mL) was added portionwise pyridinium tribromide (12.3 g, 38.6 mmol, 1.05 eq). The reaction mixture was stirred at -50°C to -40°C for 30 minutes, then allowed to warm to room temperature and stirred overnight. The reaction mixture was extracted with DCM and 1M aq. HCl. The organic layer was washed with 1M aqueous HCl and brine. The aqueous layer was back extracted three times with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 220 g, gradient: 0% to 20% ethyl acetate in heptane) to afford the title compound (4.59 g, 55% yield) as an off-white solid. LC-MS: m/z = 214.9/216.9 (Br isotope) [M+H] ⁺ , ESI pos.

step E. : 4- Benzyloxy -5- bromine -2,3- Dihydrobenzofuran

To a solution of 5-bromo-2,3-dihydrobenzofuran-4-ol (4.59 g, 20.26 mmol, 1.0 eq) in acetonitrile (40 mL) was added potassium carbonate (5.6 g, 40.51 mmol, 2.0 eq) and bromotoluene (4.89 g, 3.4 mL, 28.57 mmol, 1.4 eq). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate (140 mL) and water (30 mL). The aqueous layer was back extracted with ethyl acetate (140 mL). The organic layer was washed with water (20 mL) and brine (20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was absorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 220 g, gradient: 0% to 10% ethyl acetate in heptane) to give the title compound (6.17 g , yield 95%). LC-MS: m/z = 305.1/307.0 (Br isotope) [M+H] ⁺ , ESI pos.

step f : 2-(4- Benzyloxy -2,3- Dihydrobenzofuran -5- base )-4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane

Add 4-benzyloxy-5-bromo-2,3-dihydrobenzofuran (6.16 g, 19.18 mmol, 1.0 eq) and 2-isopropoxy-4,4,5 at -76°C within 40 minutes ,5-Tetramethyl-1,3,2-dioxaborolane (5.47 g, 6 mL, 29.41 mmol, 1.5 eq) was added dropwise in 1.6 M n-butyl A solution of Lithium in hexane (19 mL, 30.4 mmol, 1.6 eq). Stir at -76°C for 2.5 hours. The reaction mixture was warmed to -60 °C, quenched with -60 °C saturated aqueous NH4Cl (40 mL), warmed to room temperature, then extracted with ethyl acetate (300 mL) and saturated aqueous _NH4Cl (40 mL) . The aqueous layer was back extracted with ethyl acetate (300 mL). The organic layer was washed with brine (80 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was absorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 120 g, gradient: 0% to 10% ethyl acetate in heptane) to give the title compound (5.78 g , yield 81%). LC-MS: m/z = 353.1 [M+H] ⁺ , ESI pos.

step G : 5-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base )-2,3- Dihydrobenzofuran -4- alcohol

2-(4-Benzyloxydihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.77 g , 15.6 mmol, 1.0 eq) in ethyl acetate (70 mL) was alternately evacuated and flushed with argon three times. Palladium on activated carbon (10% Pd based) (577 mg, 0.542 mmol, 0.035 eq) was added carefully. The reaction flask was evacuated, flushed with argon, evacuated, and flushed with hydrogen. The reaction mixture was stirred at room temperature under hydrogen gas (balloon) for 3 hours. LC/MS showed starting material remained and methanol (10 mL) was added. The reaction flask was alternately evacuated and flushed three times with argon, evacuated and flushed with hydrogen. The reaction mixture was stirred at room temperature under hydrogen gas (balloon) for 1 h. Then, the reaction mixture was filtered and rinsed well with ethyl acetate/methanol. The filtrate was concentrated in vacuo to afford the title compound (4.22 g, 98% yield) as an off-white solid. LC-MS: m/z = 263.2 [M+H] ⁺ , ESI pos.

step h : 5-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ]-6- methyl - zozolo [4,5- b ] pyridine -5- base ]-2,3- Dihydrobenzofuran -4- alcohol

To 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dihydrobenzofuran-4-ol (106.7 mg, 0.407 mmol, 1.50 eq) In a solution in 1,4-dioxane (1.85 mL), add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (26.6 mg, 0.033 mmol, 0.120 eq) and the above 5-chloro- N -[(3 R )-1-ethyl-3-piperidinyl]-6-methyl- Zazolo[4,5- b ]pyridin-2-amine (156.2 mg, 0.271 mmol, 1.00 eq) and water (0.923 mL). The reaction was flushed with argon for 5 minutes, then potassium carbonate (168.8 mg, 1.22 mmol, 4.50 eq) was added. The reaction was stirred overnight at 100 °C. After complete conversion, the reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The aqueous layer was back extracted twice with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was absorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 10% methanol in dichloromethane). The product and by-products could not be separated. All fractions containing product were combined and concentrated in vacuo. The crude product (60 mg) was treated with preparative HPLC (YMC-Triart C ₁₈ , 12 nm, 5 µm, 100 x 30 mm, ACN/water+0.1% TEA) to give the title compound (10 mg, 9%) and gray solid by-product 5-[2-[[(3 R )-1-ethyl-3-piperidinyl]amino]oxazolo[4,5- b ]pyridin-5-yl ] Dihydrobenzofuran-4-ol (25 mg, 23% yield). LC-MS (title compound) m/z 393.2 [MH] ⁻ , ESI neg. Example 36 : 5- cyclopropyl -3- methyl -2-[2-[[(3R)-1- methyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridine -5- yl ] phenol

step A : 3- Cyclopropyl -5- methyl - phenol

3-Bromo-5-methylphenol (5.0 g, 26.73 mmol, 1.0 eq), K ₂ CO ₃ (7.39 g, 53.47 mmol, 2.0 eq) and cyclopropylboronic acid (6.89 g, 80.2 mmol, 3.0 eq) A mixture in 1,4-dioxane (50 mL) and water (10 mL) was evacuated and backfilled three times with _N2 , and Pd(dppf) _Cl2 (1956.16 mg, 2.67 mmol, 0.1 eq) was added to the mixture middle. The mixture was stirred at 100°C for 12 hours. The mixture was poured into 1N HCl (200 mL), then extracted with ethyl acetate (40 mL × 3), the combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrated under reduced pressure, the residue was purified by silica gel column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 10/1), and purified by C18 column chromatography (in water/ 0.1% TFA in MeCN). After lyophilization, 3-cyclopropyl-5-methyl-phenol was obtained as a yellow oil (1.7 g, 43% yield). ¹ H NMR (400 MHz, CD ₃ OD) δ 6.37 (s, 2H), 6.27 (s, 1H), 2.20 (s, 3H), 1.80 - 1.72 (m, 1H), 0.91 - 0.84 (m, 2H) , 0.62 - 0.57 (m, 2H).

step B : 5- Cyclopropyl -2- iodine -3- methyl - phenol

To _a mixture of 3-cyclopropyl-5-methyl-phenol (1.20 g, 8.1 mmol, 1.0 eq) in toluene (100 mL) was added NaH (388.66 mg, 16.19 mmol, 60% w/w, 2.0 eq), filtered for 30 minutes, then added I ₂ (1.64 g, 6.48 mmol, 0.8 eq) and stirred at 25°C for 15.5 hours. The mixture was poured into 1N HCl (100 mL) and extracted with ethyl acetate (60 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) and by C18 column chromatography (0.1% TFA in water/MeCN). After lyophilization, 2-iodo-3,5-dimethyl-phenol was obtained as a yellow solid (6.9 g, 34% yield). ¹ H NMR (400 MHz, CD ₃ OD) δ 6.53 (d, 1H), 6.36 (d, 1H), 2.35 (s, 3H), 1.77 (dd, 1H), 0.94 - 0.89 (m, 2H), 0.65 - 0.57 (m, 2H)

step C : 1- Benzyloxy -5- Cyclopropyl -2- iodine -3- methyl - benzene

To a solution of 5-cyclopropyl-2-iodo-3-methyl-phenol (350.0 mg, 1.28 mmol, 1.0 eq) in DMF (7 mL) was added K ₂ CO ₃ (352.94 mg, 2.55 mmol , 2.0 eq), then bromotoluene (0.46 mL, 3.83 mmol, 3.0 eq) was added dropwise, and the reaction mixture was stirred at 25°C under nitrogen atmosphere for 2 hours. The reaction was quenched with water (50 mL), extracted with EA (100 mL × 3), washed with brine (20 mL), the organic layer was dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20:1) to obtain 1-benzyloxy-5-cyclopropyl-2-iodo-3- Methyl-benzene (450 mg). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.42 (d, 2H), 7.29 (d, 2H), 7.22 (d, 1H), 6.55 (d, 1H), 6.38 (d, 1H), 5.01 (s , 2H), 2.29 (s, 3H), 1.78 - 1.68 (m, 1H), 0.88 - 0.81 (m, 2H), 0.80 - 0.74 (m, 2H), 0.58 - 0.51 (m, 2H)

step D. : 2-(2- Benzyloxy -4- Cyclopropyl -6- methyl - Phenyl )-4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane

Under N ₂ , 1-benzyloxy-5-cyclopropyl-2-iodo-3-methyl-benzene (250.0 mg, 0.69 mmol, 1.0 eq) and 2-isopropoxy-4 ,4,5,5-Tetramethyl-1,3,2-dioxaborolane (229.88 mg, 1.24 mmol, 1.8 eq) was added dropwise to a mixture of nBuLi (0.41 mL, 1.03 mmol, 1.5 eq). Then, the mixture was stirred at -60°C for 30 minutes. The mixture was poured into NH ₄ Cl solution (15 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1) to obtain 2-(2-benzyloxy-4-cyclopropyl-6-methyl-benzene as colorless oil base)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (250.0 mg). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.47 (d, 2H), 7.38 - 7.25 (m, 3H), 6.49 (d, 2H), 5.00 (s, 2H), 2.27 (s, 3H), 1.84 (dd, 1H), 1.27 (s, 12H), 0.96 - 0.84 (m, 3H), 0.68 - 0.62 (m, 2H).

step E. : 5-(2- Benzyloxy -4- Cyclopropyl -6- methyl - Phenyl )- N -[(3 R )-1- methyl -3- piperidinyl ] zozolo -[4,5- b ] pyridine -2- amine

2-(2-Benzyloxy-4-cyclopropyl-6-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (105.36 mg, 0.29 mmol, 2.0 eq), K ₂ CO ₃ (39.97 mg, 0.29 mmol, 2.0 eq) and 5-bromo- N -[(3 R )-1-methyl-3-piperidinyl]㗁Azolo[4,5- b ]pyridin-2-amine (45.0 mg, 0.14 mmol, 1.0 eq) in 1,4-dioxane (1 mL) and water (0.2 mL) was degassed and washed with N ₂ was purged three times and Pd(dppf)Cl ₂ (10.58 mg, 0.01 mmol, 0.1 eq) was added to the mixture. The mixture was stirred at 90°C for 2 hours. The reaction was quenched with water (20 mL), extracted with EA (20 mL × 3), washed with brine (20 mL), the organic layer was dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to give The title compound as a yellow oil (30.0 mg, 36% yield). LC-MS: m/z 469.3 [M+H] ⁺ , ESI pos.

step f : 5- Cyclopropyl -3- methyl -2-[2-[[(3 R )-1- methyl -3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ] phenol

5-(2-benzyloxy-4-cyclopropyl-6-methyl-phenyl) -N -[(3 R )-1-methyl-3-piperidinyl]oxazolo[4, 5-b] A solution of pyridin-2-amine (15.0 mg, 0.03 mmol, 1.0 eq) in DCM (0.5 mL) and _BBr3 (0.5 mL, 0.6 mmol, 4.39 eq) was added to the mixture. The mixture was stirred at -65°C for 1 hour. Ice cubes were first added to the reaction solution, and then methanol was slowly added to quench the reaction. Finally, ammonia is used to adjust the pH. The mixture was concentrated under reduced pressure and purified by reverse phase flash chromatography (0.1% TFA), and then by reverse phase flash chromatography (0.1% TFA) and preparative HPLC (method column 3_Phenomenex Luna C18 75 × 30mm × 3um, conditions: water (TFA)-ACN, B 16 at the start, B 36 at the end, gradient time (min) 8; 100% B hold time (min) 2; flow rate (mL/min) 25; injection 1 HPLC 99) Purification. After lyophilization, the title compound was obtained as a yellow solid (2.77 mg, 5% yield). LC-MS: m/z 379.2 [M+H] ⁺ , ESI pos. Examples 37a and 37b : 2-[2-[(3aS,7aR)-6- Methyl - 3,3a,4,5,7,7a- hexahydro -2H- pyrrolo [2,3-c] pyridine- 1- yl ] oxazolo [4,5-b] pyridin -5- yl ]-3- methyl -5-( trifluoromethyl ) phenol or 2-[2-[(3aR,7aS)-6- Methyl -3,3a,4,5,7,7a- hexahydro -2H- pyrrolo [2,3-c] pyridin -1- yl ] oxazolo [4,5-b] pyridin -5- yl ]-3- methyl -5-( trifluoromethyl ) phenol and 2-[2-[(3aR,7aS)-6- methyl -3,3a,4,5,7,7a- hexahydro -2H -pyrrolo [2,3-c] pyridin -1- yl ] oxazolo [4,5-b] pyridin - 5- yl ]-3- methyl -5-( trifluoromethyl ) -phenol or 2 -[2-[(3aS,7aR)-6- Methyl -3,3a,4,5,7,7a- hexahydro -2H- pyrrolo [2,3-c] pyridin -1- yl ] oxazole And [4,5-b] pyridin -5- yl ]-3- methyl -5-( trifluoromethyl ) phenol

In a sealed tube, 5-chloro-2-(6-methyl-3,3a,4,5,7,7a-hexahydro- 2H -pyrrolo[2,3- c ]pyridin-1-yl)oxazolo[4,5- b ]pyridine ( Example 20 , Step 1 ) (70 mg, 237 µmol, 1.00 eq) and 3-methyl-2-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS # 2557358-06-0, 107.3 mg, 88.7 µL, 355 µmol, 1.50 eq) To a yellow suspension in 1,4-dioxane (2.4 mL) and water (0.60 mL) was added cesium carbonate (231 mg, 710 µmol, 3.00 eq) and then added under argon gas XPhos Pd G3 (20.0 mg, 23.7 µmol, 0.10 eq). Argon was then bubbled through the yellow reaction mixture for 3 min. The dark yellow reaction mixture was heated to 100 °C (oil bath) for 16 hours. The black reaction mixture was cooled to room temperature and extracted twice with ethyl acetate (2 times, about 50 mL). The organic layer was washed with water (about 20 mL) and brine (about 20 mL). The aqueous layer was re-extracted with ethyl acetate (about 40 mL). The combined organic extracts were dried over sodium sulfate, filtered off and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel; 0% to 10% methanol in dichloromethane) to give the title compound (86 mg, 76%) as a light brown foam , submit it directly to chiral separation (column: chiral IJ, 5 µm, 250 × 20 mm, flow rate: 90 mL/min; SFC). LC-MS: m/z 433.2 [M+H] ⁺ , ESI pos; to give the first fraction 37a (39 mg, 43% yield) and the second fraction 37b (37 mg, 40% yield), both All are light brown foam. LCMS m/z: 433.2 433.2 [M+H] ⁺ , ESI pos. Example 38 : ( racemic )-3- methyl -2-[2-( tetrahydrofuran -3- ylamino ) oxazolo [4,5- b ] pyridin -5- yl ]-5-( trifluoro methyl ) phenol

step A : 5- chlorine - N - Tetrahydrofuran -3- base - zozolo [4,5- b ] pyridine -2- amine

5-Chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 131 mg, 0.62 mmol, 1.0 eq) in extra dry 1,4-diox Commercially available tetrahydrofuran-3-ylamine (CAS # 88675-24-5, 64.8 mg, 63.6 µL, 0.744 mmol, 1.20 eq) and triethylamine (81.6 mg , 112 µL, 0.806 mmol, 1.30 eq). The light brown solution was stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (30 mL) and saturated NaHCO ₃ solution (15 mL). The aqueous layer was back extracted with ethyl acetate (30 mL). The organic layer was washed with water (10 mL) and brine (10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography ( _Si02 ; 0% to 90% ethyl acetate in heptane) to afford the title compound (133 mg, 90%) as a white solid. LC-MS: m/z 240.1; 242.1 (Cl isotope) [M+H]+, ESI pos

step B : ( Racemization )-3- methyl -2-[2-( Tetrahydrofuran -3- Amino ) zozolo [4,5-b] pyridine -5- base ]-5-( Trifluoromethyl ) phenol

In a sealable tube, the above (5-chloroazolo[4,5- b ]pyridin-2-yl)-tetrahydrofuran-3-yl-amine (40 mg, 0.167 mmol, 1.00 eq), [2- Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]boronic acid (CAS # 2557358-06-0, 51.4 mg, 0.234 mmol, 1.40 eq) and potassium carbonate (103.8 mg, 0.751 mmol, 4.50 eq) Stir in 1,4-dioxane (2.29 mL) and water (1.14 mL). Argon was bubbled through the mixture for 2 minutes, and finally the catalyst 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(ii) dichloromethane complex (16.4 mg, 0.02 mmol , 0.12 eq). The sealed tube was stirred at 90°C for 16 hours. The reaction mixture was extracted with ethyl acetate (2 x 20 mL) and half saturated NH ₄ Cl solution (20 mL). The organic layer was washed with water (20 mL) and brine (20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue (112 mg) was submitted to preparative RP HPLC (column: YMC-triart C ₁₈ , 12 nm, 5 µm, 100 × 30 mm; CAN/water + 0.1% HCOOH) to give a white amorphous lyophilized The title compound (5 mg, 8%) as a solid. LC-MS: m/z 380.2 [M+H] ⁺ , ESI pos. Examples 39 , 40 and 41 : 5- Chloro -3- methyl -2-[2-[[ rac- (8S,8aR)-1,2,3,5,6,7,8,8a -eta Hydroindolizin -8- yl ] amino ] oxazolo [4,5-b] pyridin -5- yl ] phenol, 2-[2-[[(8R,8aS)-1,2,3,5, 6,7,8,8a -Swainson -8- yl ] amino ] oxazolo [4,5-b] pyridin -5- yl ]-5- chloro -3- methyl - phenol and 2- [2-[[(8S,8aR)-1,2,3,5,6,7,8,8a- swainson -8- yl ] amino ] oxazolo [4,5-b] pyridine -5- yl ]-5- chloro -3- methyl - phenol

step A : 5- chlorine -N- [ Racemization -(8S,8aR)-1,2,3,5,6,7,8,8a- Swainsonine -8- base ] zozolo [4,5-b] pyridine -2- amine

To the above 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 150 mg, 0.710 mmol, 1.00 eq) in 1,4-dioxane (1.5 mL) was sequentially added [ rac- (8R,8aS)-indolizin-8-yl]amine (CAS # 1993250-73-9, 115.9 mg, 0.785 mmol, 1.106 eq) and tris Ethylamine (111 µL, 0.796 mmol, 1.121 eq). The light brown solution was stirred overnight at 90°C. The reaction mixture was stirred for a further 4 hours at 100°C. A precipitate formed which was triturated in ether to give the desired product (105 mg, 51%) as a white solid. LC-MS: m/z 293.2 [M+H] ⁺ , ESI pos.

step B : 2-[2-(1,2,3,5,6,7,8,8a- Swainsonine -8- Amino ) zozolo [4,5-b] pyridine -5- base ]-5- chlorine -3- methyl - phenol ( racemic trans )

The above 5-chloro- N- [ rac- (8S,8aR)-1,2,3,5,6,7,8,8a-swainson-8-yl]oxazolo[4, 5- b ]pyridin-2-amine ( Step A ) (105 mg, 0.359 mmol, 1.00 eq), (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (CAS # 1207961-50-9 , 96.3 mg, 0.516 mmol, 1.440 eq) 1.44 eq), cesium carbonate (172.9 mg, 0.531 mmol, 1.48 eq) and Xphos-Pd-G3 (31.3 mg, 0.037 mmol, 0.103 eq) in 1,4-dioxane (1.5 mL) and water (0.375 mL) was flushed with argon and stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature and extracted with about 30 mL of ethyl acetate and about 5 mL of water. The aqueous layer was back extracted with about 30 mL of ethyl acetate. The organic layer was washed with about 5 mL of water and about 5 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was absorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 10% (methanol + 2% _NH4OH ) in dichloromethane) to give a pale yellow powder as the title compound (34 mg). LC-MS: m/z 397.3 [MH]-, ESI neg.

Step C: 2-[2-[[(8 R ,8a S )-1,2,3,5,6,7,8,8a- swainson -8- yl ] amino ] oxazolo [ 4,5-b] pyridin -5- yl ]-5- chloro -3- methyl - phenol or 2-[2-[[(8 S ,8a R )-1,2,3,5,6,7 ,8,8a- Swainson -8- yl ] amino ] oxazolo [4,5-b] pyridin -5- yl ]-5- chloro -3- methyl - phenol and 2-[2- [[(8 S ,8a R )-1,2,3,5,6,7,8,8a- swainson - 8- yl ] amino ] oxazolo [4,5-b] pyridine- 5- yl ]-5- chloro -3- methyl - phenol or 2-[2-[[(8 R ,8a S )-1,2,3,5,6,7,8,8a- octahydroindoline Azin -8- yl ] amino ] oxazolo [4,5-b] pyridin -5- yl ]-5- chloro - 3- methyl - phenol

The mixed fractions were purified by RP HPLC (SFC, 20% to 40% MeOH+0.2% DEA, column AD-H) to obtain two fractions: the first ( Example 41 ) was washed at retention time = 3.11 minutes (11.7 mg, 100% ee) and the second ( Example 40 ) (13 mg, 100% ee) were eluted at retention time = 3.97 min, both as light brown solids. LC-MS: m/z 397.3 [MH]-, ESI neg. Example 42 : 5- Chloro -3- methyl -2-[2-(6- methyl -3,4a,5,7,8,8a- hexahydro - 2H - pyrido [4,3- b ] [1,4] oxazin -4- yl ) oxazolo [4,5-b] pyridin -5- yl ] phenol

step A : 4-(5- Chlorazolo [4,5-b] pyridine -2- base )-6- methyl -3,4a,5,7,8,8a- Hexahydro -2H- pyrido [4,3-b][1,4] oxazine

5-Chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 242 mg, 1.21 mmol, 1.00 eq) and 6-methyl- 2,3,4,4a,5,7,8,8a-octahydropyrido[4,3- b ][1,4]oxazine (245 mg, 1.57 mmol, 1.30 eq) in extra dry 1,4 - To a mixture of dioxane (4 mL) and extra dry N -methyl-2-pyrrolidone (2 mL) was added triethylamine (244 mg, 336 µL, 2.41 mmol, 2.00 eq). The reaction mixture was stirred at 110 °C for 16 hours in a sealed tube. The reaction was incomplete, so the temperature was increased to 150°C and stirring was continued for 4 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with water (30 mL) and brine (30 mL). The combined organic extracts were dried over sodium sulfate, filtered off and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 50% ethyl acetate in heptane; then ethyl acetate:methanol 9:1 (v/v)) to give the title as a light brown foam Compound (233 mg, 63%). LC-MS: m/z 309.1 ([{35Cl}M+H]+), 311.1 ([{37Cl}M+H]+), ESI pos.

step B : 5- chlorine -3- methyl -2-[2-(6- methyl -3,4a,5,7,8,8a- Hexahydro -2H- pyrido [4,3-b][1,4] oxazine -4- base ) zozolo [4,5-b] pyridine -5- base ] phenol

In a sealable tube, the above 4-(5-chloroazolo[4,5-b]pyridin-2-yl)-6-methyl-3,4a,5,7,8,8a-hexa Hydrogen-2H-pyrido[4,3-b][1,4]oxazine (73 mg, 0.236 mmol, 1.00 eq), (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid ( CAS # 1207961-50-9, 88.1 mg, 0.473 mmol, 2.00 eq) and potassium carbonate (147 mg, 1.06 mmol, 4.50 eq) in 1,4-dioxane (2 mL) and water (1 mL) The mixture was stirred and argon was bubbled through the mixture for 2 minutes, and finally the catalyst 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloromethane complex was added ( 28.9 mg, 0.035 mmol, 0.15 eq). The sealed tube was stirred at 100°C for 16 hours. The reaction mixture was extracted with ethyl acetate (2 x 20 mL) and half saturated NH ₄ Cl solution (20 mL). The organic layer was washed with water (30 mL) and brine (30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue (110 mg) was purified by flash chromatography (silica gel, gradient: 0% to 100% in dichloromethane (dichloromethane:methanol:NH ₄ OH 110:10:1)) and then in Further purification on preparative HPLC gave the title compound (4 mg, 4%) as a white amorphous lyophilized solid. LC-MS: m/z 413.1 ([{35Cl}MH] ⁺ ), 415.1 ([{37Cl}MH] ⁺ ), ESI neg. Example 43 : 2-[2-(2- Azabicyclo [2.1.1] hex -1- ylmethylamino ) oxazolo [4,5- b ] pyridin -5- yl ]-3- methyl -5-( Trifluoromethyl ) phenol; Dihydrochloride

step A : 1-[[(5- Chlorazolo [4,5-b] pyridine -2- base ) Amino ] methyl ]-2- Azabicyclo [2.1.1] Hexane -2- Tertiary butyl formate

5-Chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 111 mg, 553.2 umol, 1.000 eq) and triethylamine (112 1- ( Aminomethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (153 mg, 719 µmol, 1.30 eq). The reaction mixture was stirred at 120°C for 16 hours in a sealed tube. The temperature was increased to 150°C and stirring was continued for 2 hours until complete conversion. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with water (30 mL) and brine (30 mL). The combined organic extracts were dried over sodium sulfate, filtered off and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 50% ethyl acetate in heptane) to afford the title compound (156 mg, 77.29%) as a pale yellow solid. LC-MS: m/z 365.2 ([{35Cl}M+H]+), 367.2 ([{37Cl}M+H]+), ESI pos.

step B : 1-[[[5-[2- hydroxyl -6- methyl -4-( Trifluoromethyl ) Phenyl ] zozolo [4,5- b ] pyridine -2- base ] Amino ] methyl ]-2- Azabicyclo [2.1.1] Hexane -2- Tertiary butyl formate

The above 1-[[(5-chloroazolo[4,5-b]pyridin-2-yl)amino]methyl]-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tri Butyl ester (154 mg, 422 µmol, 1.00 eq), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- A mixture of -5-(trifluoromethyl)phenol (283.4 mg, 844 µmol, 2.000 eq) and potassium carbonate (280 mg, 2.03 mmol, 4.80 eq) was dissolved in 1,4-dioxane (4 mL) and water (2 mL). The sealable tube was flushed with argon and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(ii)dichloromethane complex (51.7 mg, 63.3 µmol, 0.15 eq) was added . Flush again with argon and stir the sealed tube at 100°C (oil bath) for 16 hours. Under argon, methanesulfonate (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1, 1'-biphenyl-2-yl) palladium (ii) (XPhos Pd G3) (71.5 mg, 84.4 µmol, 0.20 eq) and cesium carbonate (137.5 mg, 422 µmol, 1.00 eq), and in 110 ℃ (oil bath ) and continue stirring for another 4 hours. The reaction mixture was cooled to room temperature and quenched with water (20 mL) and saturated NH ₄ Cl solution (20 mL), then extracted with dichloromethane (3×30 mL). The organic layer was washed with brine (40 mL), dried over Na ₂ SO ₄ , filtered off and concentrated in vacuo. The residue was purified by flash chromatography ( _Si02 ; 0% to 50% ethyl acetate in heptane), then triturated in heptane to afford the title compound (91 mg, 43%) as a white solid. LC-MS: m/z 505.3 [M+H]+, ESI pos.

step C : 2-[2-(2- Azabicyclo [2.1.1] Has -1- methylamino ) zozolo [4,5-b] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) Phenol; dihydrochloride

To the above 1-[[[5-[2-hydroxyl-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5- b ]pyridin-2-yl]amine at room temperature tert-butyl]methyl]-2-azabicyclo[2.1.1]hexane-2- carboxylate (89 mg, 176 µmol, 1.00 eq) in dichloromethane (4 mL) and methanol (2 mL) To the solution in 4 M HCl in dioxane (441 µL, 1.76 mmol, 10.0 eq) was added dropwise. The reaction mixture was stirred at 23 °C for 20 hours. The reaction mixture was concentrated in vacuo, then crystallized from EtOH/EA/heptane to afford the title compound as a 1:2 hydrochloride salt (74 mg, 83%) as a white solid. LC-MS: m/z 403.2 [MH]-, ESI neg. Example 44 : 5- Chloro -3- methyl -2-[2-[[(3 R )-1- methyl -3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridine- 5- yl ] phenol

The title compound was obtained as a light brown powder, LCMS: m/z 373.2 [M+ H ] ⁺ , ESI pos, from 5-chloro- N -[( 3R )- 1-methyl-3-piperidinyl]oxazolo[4,5- b ]pyridin-2-amine ( Example 15 , step 1 ) and (4-chloro-2-hydroxy-6-methyl-phenyl ) boric acid ( CAS # 1207961-50-9 ) was prepared. Example 45 : 2-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridin - 5- yl ]-5- fluoro- 3- Methyl - phenol

The title compound was obtained as a pale yellow solid, LCMS: m/z 371.3 [M+H] ⁺ , ESI pos, from 5-chloro- N -[( 3R )- 1-Ethyl-3-piperidinyl]oxazolo[4,5- b ]pyridin-2-amine ( Example 14 , step 1) and (4-fluoro-2-hydroxy-6-methyl-phenyl ) boronic acid ( intermediate A ) (see preparation method below) to start the preparation. Intermediate A : (4- fluoro -2- hydroxy -6- methyl - phenyl ) boronic acid

step A : 2- bromine -4- fluorine -6- methyl - aniline

A solution of 4-fluoro-2-methyl-aniline (CAS # 452-71-1, 200 g, 1.60 mol) in DMF (3000 mL) was cooled to -10°C, then added in portions below 30°C N -Bromosuccinimide (313 g, 1.76 mol, 1.1 eq). After the addition, the mixture was stirred at 25°C for 3 hours. The reaction mixture was dissolved in H ₂ O (6000 mL), then extracted with EtOAc (2000 mL×2). The organic layer was washed with brine (1000 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (230 g, 71% yield) as a purple liquid. LCMS m/z 204.0, [M+H] ⁺ , ESI pos.

step B : 4- fluorine -2- Methoxy -6- methyl - aniline

To the above solution of 2-bromo-4-fluoro-6-methyl-aniline (230 g, 1.13 mol) in MeOH (460 mL) was added sodium methoxide (1150 mL, 5.75 mol) and cuprous iodide (236 g, 1.24 mol). The mixture was then stirred at 65°C for 4 hours. The mixture was quenched with NH ₄ Cl (sat. aq., 3000 mL), then filtered, and the solution was extracted with EtOAc (2000 mL×2). The organic layer was washed with brine (1000 mL), dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by chromatography (silica gel, petroleum ether:ethyl acetate=10:1 to 5:1) to obtain the title compound (127 g, yield 73%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 6.47 (td, 2 H), 3.84 (s, 3 H) 2.17 (s, 3 H).

step C : 5- fluorine -2- iodine -1- Methoxy -3- methyl - benzene

To a mixture of tetrafluoroboric acid (317 g, 1.44 mol, 40% in water) and water (160 mL) was added the above 4-fluoro-2-methoxy-6-methyl-aniline (80.0 g, 516 mmol), then the mixture was cooled to 0°C to 5°C, and EtOH (80.0 mL) was added. Then a mixture of sodium nitrite (39.1 g, 567 mmol) in water (80.0 mL) was added dropwise to the reaction solution at 0°C to 5°C. After the addition, the mixture was stirred at 0°C to 5°C for 0.5 hours. The mixture was filtered and the filter cake was collected and dissolved in water (400 mL). A solution of potassium iodide (128 g, 773 mmol) in water (400 mL) was then added dropwise at 10°C to 20°C. After the addition, the reaction mixture was stirred at 20°C to 30°C for 1 hour. The mixture was extracted with EtOAc (500 mL x 2), then the organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1:0 to 10:1) to obtain the title compound (62.6 g, yield 46%) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 6.59 - 6.73 (m, 1H), 6.42 (dd, 1H), 3.86 (s, 3H) 2.46 (s, 3H).

step D. : 2-(4- fluorine -2- Methoxy -6- methyl - Phenyl )-4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane

The above 5-fluoro-2-iodo-1-methoxy-3-methyl-benzene (70.0 g, 263 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1 , A solution of 3,2-dioxaborolane (97.9 g, 526 mmol) in THF (350 mL) was cooled to -20 °C under _N2 , and then isopropylmagnesium chloride was added below -10 °C - Lithium chloride (243 mL, 316 mmol). After the addition, the reaction mixture was warmed to 20°C to 30°C and stirred for 1 hour. The mixture was quenched with saturated aqueous NH ₄ Cl (350 mL) and extracted with EtOAc (300 mL×2), the organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a residue. The residue was slurried with n-heptane (140 mL) at 0°C to 10°C for 0.5 h, then filtered, and the filter cake was dried in vacuo to give the title compound as an off-white solid (46.0 g, 173 mmol, yield 66%). ¹ H NMR (400 MHz, CDCl ₃ ): δ = 6.46 (dd, 1H), 6.37 (dd, 1H), 3.74 (s, 3H), 2.34 (s, 3H), 1.38 (s, 12H).

step E. : (4- fluorine -2- hydroxyl -6- methyl - Phenyl ) boric acid

The above-mentioned 2-(4-fluoro-2-methoxy-6-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane ( 46.0 g, 173 mmol) in dichloromethane (460 mL) was cooled to -20°C to 0°C, then boron tribromide (86.6 g, 346 mmol) below 0°C was added. The reaction mixture was stirred at -20°C to 0°C for 0.5 hours. The reaction mixture was quenched with MTBE (120 mL) below 0 °C. The mixture was then filtered and the filter cake was collected and slurried with _H2O (80 mL) at 15°C to 25°C for 0.5 h. The mixture was then filtered, and the filter cake was washed with H ₂ O (20 mL). The filter cake was dried under vacuum at 30°C to 35°C. The residue was slurried with EtOAc (40 mL) and n-heptane (80 mL) at 20°C to 30°C for 0.5 h, then filtered and the filter cake was dried in vacuo at 30°C to 35°C to give a white solid The title compound (13.2 g, 45% yield). ¹ H NMR (400 MHz, CDCl ₃ ): δ = 6.40 (dd, 1 H), 6.30 (dd, 1 H), 2.20 (s, 3 H). Example 46 : 5- Chloro -3- methyl -2-[2-[[(3 R )-1- propyl - 3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridine- 5- yl ] phenol

step 1 : N -[(3 R )-1- Propyl -3- piperidinyl ] Tertiary butyl carbamate

To a solution of tert-butyl N -[(3 R )-3-piperidinyl] carbamate (CAS # 309956-78-3, 1.00 g, 4.99 mmol, 1.00 eq) in tetrahydrofuran (20 mL) was added N , N -Diisopropylethylamine (1.63 g, 2.2 mL, 12.6 mmol, 2.52 eq) was then added dropwise 1-iodopropane (1.01 g, 0.580 mL, 5.95 mmol, 1.19 eq). The solution was stirred at 40°C for 16 hours. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHCO ₃ , and extracted with ethyl acetate. The aqueous layer was back extracted twice with ethyl acetate. The organic layer was washed with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 10% methanol in dichloromethane) to give the title compound (1.14 g, yielding rate 89%). LCMS: m/z 243.2 [M+H] ⁺ , ESI pos.

step 2 : (3 R )-1- Propylpiperidine -3- Amine hydrochloride

To tert- butyl N -[( 3R )-1-propyl-3-piperidinyl]carbamate ( Example 46 , Step 1 ) (320 mg, 1.25 mmol, 1.00 eq) in dichloromethane (3.2 mL ) and methanol (1.6 mL) was added dropwise with 4 M HCl in dioxane (3.0 mL, 12.0 mmol, 9.57 eq). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to afford the title compound (408 mg, 91% yield, 50% purity) as a pale yellow oil. LCMS: m/z 143.2 [M+H] ⁺ , ESI pos.

step 3 : 5- chlorine - N -[(3 R )-1- Propyl -3- piperidinyl ] zozolo [4,5- b ] pyridine -2- amine

To 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 220 mg, 1.04 mmol, 1.00 eq) in 1,4-dioxane ( 2.0 mL) were added ( 3R )-1-propylpiperidin-3-amine hydrochloride ( Example 46 , step 2 ) (402 mg, 1.12 mmol, 1.08 eq, purity 50%) and three Ethylamine (366 mg, 0.504 mL, 3.62 mmol, 3.47 eq). The reaction mixture was stirred at 90 °C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated NaHCO ₃ solution. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient: 0% to 10% methanol in dichloromethane) to give the title compound (274 mg, yield 85%). LCMS: m/z 295.1 [M+H] ⁺ , ESI pos.

step 4 : 5- chlorine -3- methyl -2-[2-[[(3 R )-1- Propyl -3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ] phenol

The title compound was obtained as a pale yellow foam, LCMS: m/z 401.2 [M+H] ⁺ , ESI pos, from 5-chloro- N -[( 3R )- 1-propyl-3-piperidinyl]oxazolo[4,5- b ]pyridin-2-amine ( Example 46 , step 3 ) and (4-chloro-2-hydroxy-6-methyl-phenyl ) boric acid ( CAS # 1207961-50-9 ) was prepared. Example 47 : 5- Chloro -2-[2-[[(3 R )-1- cyclobutyl -3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridin -5- yl ] -3- Methyl - phenol

step 1 : N -[(3 R )-1- Cyclobutyl -3- piperidinyl ] Tertiary butyl carbamate

To a solution of cyclobutanone (CAS# 1191-95-3, 1.05 g, 14.98 mmol, 1.50 eq) in dichloromethane (22 mL) was added N -[( 3R )-3-piperidinyl]amine Tertiary-butyl formate (CAS # 309956-78-3, 2.00 g, 9.99 mmol, 1.00 eq), sodium acetate (901 mg, 10.98 mmol, 1.10 eq) and acetic acid (661 mg, 0.630 mL, 11.0 mmol, 1.10 eq ). Sodium triacetyloxyborohydride (2.75 g, 12.98 mmol, 1.30 eq) was added in three portions and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was carefully basified with saturated aqueous NaHCO ₃ and saturated aqueous Na ₂ CO ₃ , then extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 40 g, gradient: 0% to 5% methanol in dichloromethane) to afford the title compound (1.92 g , yield 72%). LCMS: m/z 255.3 [M+H] ⁺ , ESI pos.

step 2 : 5- chlorine - N -[(3 R )-1- Cyclobutyl -3- piperidinyl ] zozolo [4,5- b ] pyridine -2- amine

To tertiary butyl N -[( 3R )-1-cyclobutyl-3-piperidinyl]carbamate ( Example 47 , Step 1 ) (204 mg, 0.76 mmol, 1.15 eq) in dichloromethane (5.6 To the solution in mL) was added trifluoroacetic acid (1.63 g, 1.1 mL, 14.28 mmol, 21.5 eq) dropwise. Stir at room temperature for 3 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in 1,4-dioxane (0.800 mL), and triethylamine (363 mg, 0.500 mL, 3.59 mmol, 5.41 eq) and 5-chloro-2-(methylthio) were added sequentially. Azolo[4,5- b ]pyridine (CAS# 1783370-92-2, 140 mg, 0.66 mmol, 1.00 eq). The brown solution was stirred at 90°C for 16 hours. Triethylamine (181.5 mg, 0.250 mL, 1.79 mmol, 2.71 eq) was added at room temperature, and the reaction mixture was stirred at 100°C for 5 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated aqueous NaHCO ₃ . The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 10% methanol in dichloromethane) to give the title compound (121 mg, yield rate 57%). LCMS: m/z 307.1 [M+H] ⁺ , ESI pos.

step 3 : 5- chlorine -2-[2-[[(3 R )-1- Cyclobutyl -3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl - phenol

The title compound was obtained as a light brown powder, LCMS: m/z 413.2 [M+H] ⁺ , ESI pos, from 5-chloro- N -[( 3R )- 1-cyclobutyl-3-piperidinyl]oxazolo[4,5- b ]pyridin-2-amine ( Example 47 , step 2 ) and (4-chloro-2-hydroxy-6-methyl-benzene base) boronic acid ( CAS # 1207961-50-9 ) was prepared. Example 48 : 5-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridin -5- yl ]-6- methyl -2,3- Dihydrobenzofuran -4- ol

step 1 : 1-(2- Benzyloxy -6- hydroxyl -4- methyl - Phenyl ) ethyl ketone

1-(2,6-dihydroxy-4-methyl-phenyl)ethanone (CAS # 1634-34-0, 5.1 g, 30.69 mmol, 1.00 eq) in N,N -dimethylformamide Potassium carbonate (4.38 g, 31.69 mmol, 1.03 eq) and bromotoluene (5.46 g, 3.8 mL, 31.95 mmol, 1.04 eq) were added sequentially to the solution in (35 mL). The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was cooled to room temperature and extracted with saturated aqueous NH ₄ Cl solution and three times with dichloromethane. The organic layer was washed with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 220 g, gradient: 5% to 20% ethyl acetate in heptane) to give the title compound (4.94 g, yield 50%, purity 80%). LCMS: m/z 257.1 [M+H] ⁺ , ESI pos.

step 2 : 4- Benzyloxy -6- methyl - Benzofuran -3- ketone

1-(2-Benzyloxy-6-hydroxy-4-methyl-phenyl)ethanone ( Example 48 , step 1 ) (2.81 g, 8.77 mmol, 1.00 eq, purity 80%) at -76°C was dissolved in To a solution in THF (40 mL) was added chlorotrimethylsilane (2.91 g, 3.4 mL, 26.79 mmol, 3.05 eq) followed by dropwise addition of 1 M lithium bis(trimethylsilyl)amide in THF/ethylbenzene (18.92 g, 22 mL, 22 mmol, 2.51 eq), keeping the internal temperature below -65°C. After the addition was complete, the ice bath was removed, and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was cooled to 0°C, and N -bromosuccinimide (1.90 g, 10.68 mmol, 1.22 eq) was added in three portions at 0°C. Stir at 0 °C for 20 min and at rt for 1 h, then add 1M aqueous NaOH (10 mL, 10 mmol, 1.14 eq) and stir at rt for 1 h. Pour into ice-cold 1 M HCl solution and extract with ethyl acetate. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 80 g, gradient: 0% to 20% ethyl acetate in heptane) to give the title compound (1.63 g, yield 66%, purity 90%). LCMS: m/z 255.1 [M+H] ⁺ , ESI pos.

step 3 : 4- Benzyloxy -6- methyl -2,3- Dihydrobenzofuran -3- alcohol

To 4-benzyloxy-6-methyl-benzofuran-3-one ( Example 48 , step 2 ) (1.05 g, 3.71 mmol, 1.00 eq, purity 90%) in methanol (10 mL) and To a partial solution in tetrahydrofuran (5 mL) was added sodium borohydride (422 mg, 11.15 mmol, 3.00 eq) in three portions. The reaction mixture was stirred at 0 °C for 3 hours. The reaction mixture was quenched with water, then extracted three times with dichloromethane. The organic layer was washed with brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (1.03 g, 87% yield, 80% purity) as a light brown oil which was used without further purification. LCMS: m/z 239.1 [ _MH2O +H] ⁺ , ESI pos.

step 4 : 6- methyl -2,3- Dihydrobenzofuran -4- alcohol

Add 4-benzyloxy-6-methyl-2,3-dihydrobenzofuran-3-ol ( Example 48 , step 3 ) (1.03 g, 3.21 mmol, 1.00 eq) and methanol (32 mL). Pd(OH) ₂ /C 20% Het 60-1 (103 mg, 0.06 mmol, 0.015 eq) was added under argon. The reactor was sealed, evacuated and heated to 40° C., then backfilled with hydrogen (set reaction pressure to 5 bar). The reaction mixture was stirred at 40 °C for 18 hours. After carefully venting the reactor, the reaction mixture was filtered (Pall Acrodisc CR 25mm syringe filter 0.45 µm) and rinsed with methanol. The filtrate was concentrated to give the title compound (556 mg, 92% yield, 80% purity) as a brown oil which was used without further purification. LCMS: m/z 151.0 [M+H] ⁺ , ESI pos.

step 5 : 4- Benzyloxy -6- methyl -2,3- Dihydrobenzofuran

To a solution of 6-methyl-2,3-dihydrobenzofuran-4-ol ( Example 48 , Step 4 ) (393 mg, 2.09 mmol, 1.00 eq, 80% purity) in acetonitrile (4.4 mL) Potassium carbonate (582 mg, 4.21 mmol, 2.01 eq) and bromotoluene (546 mg, 0.38 mL, 3.20 mmol, 1.53 eq) were added sequentially. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 5% ethyl acetate in heptane) to give the title compound as a colorless oil (379 mg, yielding rate 60%, purity 80%). LCMS: m/z 241.1 [M+H] ⁺ , ESI pos.

step 6 : 4- Benzyloxy -5- bromine -6- methyl -2,3- Dihydrobenzofuran

4-Benzyloxy-6-methyl-2,3-dihydrobenzofuran ( Example 48 , Step 5 ) (377 mg, 1.26 mmol, 1.00 eq, 80% purity) was dissolved in dichloromethane ( 14 mL) was added portionwise with N -bromosuccinimide (294 mg, 1.65 mmol, 1.32 eq). The reaction mixture was stirred at 0 °C for 5.5 hours. The reaction mixture was quenched with saturated aqueous NaHCO ₃ and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was absorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 5% ethyl acetate in heptane). All fractions containing product were combined and concentrated in vacuo. The residue was taken up on ISOLUTE HM-N and purified again by flash chromatography (silica gel, gradient: 0% to 50% dichloromethane in heptane) to give the title compound as a colorless oil (370 mg, Yield 65%, purity 70%). LCMS: m/z 319.0; 321.0 (Br isotope) [M+H] ⁺ , ESI pos.

step 7 : 2-(4- Benzyloxy -6- methyl -2,3- Dihydrobenzofuran -5- base )-4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane

To 4-benzyloxy-5-bromo-6-methyl-2,3-dihydrobenzofuran ( Example 48 , step 6 ) (490 mg, 1.07 mmol, 1.00 eq, purity 70%) at -76°C and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS # 61676-62-8, 438 mg, 0.48 mL, 2.35 mmol , 2.19 eq) to a solution in tetrahydrofuran (6.4 mL) was added dropwise a 1.6 M solution of n-butyllithium in hexane (1.5 mL, 2.40 mmol, 2.23 eq). Stir at -76°C for 3 hours. The reaction mixture was warmed to -60°C, quenched with -60°C saturated aqueous _NH4Cl , warmed to room temperature, and extracted with ethyl acetate. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 10% ethyl acetate in heptane) to give the title compound as a colorless oil (305 mg, yielding rate 62%, purity 80%). LCMS: m/z 367.1 [M+H] ⁺ , ESI pos.

step 8 : 6- methyl -5-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base )-2,3- Dihydrobenzofuran -4- alcohol

2-(4-Benzyloxy-6-methyl-2,3-dihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxo A solution of borane ( Example 48 , Step 7 ) (300 mg, 0.66 mmol, 1.00 eq, 80% purity) in ethyl acetate (3.2 mL) and methanol (0.80 mL) was alternately evacuated and flushed with argon three times . Palladium on activated carbon (10% Pd based) (30 mg, 0.03 mmol, 0.04 eq) was added. The reaction flask was evacuated, flushed with argon, evacuated, and flushed with hydrogen. The reaction mixture was stirred at room temperature under hydrogen gas (balloon) for 2.5 hours. The reaction mixture was filtered and rinsed well with ethyl acetate/methanol. The filtrate was concentrated in vacuo to give the title compound (225 mg, 99% yield, 80% purity) as a colorless oil, which was used without further purification. LCMS: m/z 277.0 [M+H] ⁺ , ESI pos.

step 9 : 5-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-6- methyl -2,3- Dihydrobenzofuran -4- alcohol

The title compound was obtained as a light brown solid, LCMS: m/z 395.3 [M+H] ⁺ , ESI pos, from 5-chloro- N -[( 3R )- 1-Ethyl-3-piperidinyl]oxazolo[4,5- b ]pyridin-2-amine ( Example 14 , step 1) and 6-methyl-5-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol ( Example 48 , Step 8) was prepared starting. Example 49 : ( 3S , 5R )-5-[[5-(4- chloro -2- hydroxyl -6- methyl - phenyl ) oxazolo [4,5- b ] pyridin -2- yl ] Amino ]-1- methyl - piperidin -3- ol

step 1 : (3 R ,5 S )-3-[(5- Chlorazolo [4,5- b ] pyridine -2- base ) Amino ]-5- hydroxyl - piperidine -1- Tertiary butyl formate

To 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 200 mg, 0.95 mmol, 1.00 eq) in 1,4-dioxane ( 1.9 mL) was sequentially added (3 R ,5 S )-3-amino-5-hydroxy-piperidine-1-carboxylic acid tertiary butyl ester (CAS # 1932513-59-1, 236 mg, 1.09 mmol , 1.15 eq) and triethylamine (112 mg, 0.154 mL, 1.10 mmol, 1.17 eq). The brown solution was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated NaHCO ₃ solution. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 5% methanol in dichloromethane) to afford the title compound (257 mg , 66% yield, 90% yield). LCMS: m/z 369.1 [M+H] ⁺ , ESI pos.

step 2 : (3 S ,5 R )-5-[(5- Chlorazolo [4,5- b ] pyridine -2- base ) Amino ] piperidine -3- Alcohol hydrochloride

(3 R ,5 S )-3-[(5-Chloroxazolo[4,5- b ]pyridin-2-yl)amino]-5-hydroxy-piperidine-1-carboxylic acid tertiary butyl ester ( Example 49 , Step 1) (252 mg, 0.61 mmol, 1.00 eq, 90% purity) To a solution in dichloromethane (1.2 mL) and methanol (0.60 mL) was added dropwise 4 M HCl in dioxane (1.5 mL, 6.00 mmol, 9.76 eq). The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated in vacuo to afford the title compound (268 mg, 99% yield, 70% purity) as an off-white foam, which was used without further purification. LCMS: m/z 269.0 [M+H] ⁺ , ESI pos.

step 3 : (3 S ,5 R )-5-[(5- Chlorazolo [4,5- b ] pyridine -2- base ) Amino ]-1- methyl - piperidine -3- alcohol

To (3 S ,5 R )-5-[(5-chlorooxazolo[4,5- b ]pyridin-2-yl)amino]piperidin-3-ol hydrochloride ( Example 49 , step 2 ) (264 mg, 0.61 mmol, 1.00 eq, purity 70%) To a mixture in 1,2-dichloroethane (6.5 mL) was added triethylamine (94 mg, 0.130 mL, 0.93 mmol, 1.54 eq). Stir at room temperature for 5 minutes. 37% aqueous formaldehyde (65 mg, 0.060 mL, 0.81 mmol, 1.33 eq) and sodium triacetyloxyborohydride (386 mg, 1.82 mmol, 3.01 eq) were added sequentially. The reaction mixture was stirred at room temperature for 1 hour, then additional 37% aqueous formaldehyde (65 mg, 0.060 mL, 0.81 mmol, 1.33 eq) and sodium triacetyloxyborohydride (193 mg, 0.91 mmol, 1.50 eq ). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with dichloromethane and saturated aqueous NaHCO ₃ . The aqueous layer was back extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 20% methanol in dichloromethane) to give the title compound (146 mg, yield 81%). LCMS: m/z 283.1 [M+H] ⁺ , ESI pos.

step 4 : (3 S ,5 R )-5-[[5-(4- chlorine -2- hydroxyl -6- methyl - Phenyl ) zozolo [4,5- b ] pyridine -2- base ] Amino ]-1- methyl - piperidine -3- alcohol

The title compound was obtained as a light brown powder, LCMS: m/z 389.2 [M+H] ⁺ , ESI pos, from ( 3S , 5R )-5-[( 5-Chlorozozolo[4,5- b ]pyridin-2-yl)amino]-1-methyl-piperidin-3-ol ( Example 49 , step 3) and (4-chloro-2-hydroxy -6-Methyl-phenyl)boronic acid ( CAS# 1207961-50-9 ) was prepared initially. Example 50 : 5- fluoro -3- methyl -2-[2-[[(3 R )-1- methyl -3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridine- 5- yl ] phenol

The title compound was obtained as a light brown powder, LCMS: m/z 357.3 [M+H] ⁺ , ESI pos, from 5-chloro- N -[( 3R )-1-methyl-3-piperidinyl]oxazolo[4,5- b ]pyridin-2-amine ( Example 15 , step 1 ) and (4-fluoro-2-hydroxyl-6-methyl- Phenyl)boronic acid ( Example 45 , Intermediate A ) was prepared starting. Example 51 : ( 3S , 5R )-1- Ethyl -5-[[5-[2- hydroxy -6- methyl -4-( trifluoromethyl ) phenyl ] oxazolo [4,5 - b ] pyridin -2- yl ] amino ] piperidin -3- ol

The title compound was obtained as a pale yellow solid, LCMS: m/z 437.4 [M+H] ⁺ , ESI pos, from ( 3S , 5R )-5- [(5-Chlorozozolo[4,5- b ]pyridin-2-yl)amino]-1-ethyl-piperidin-3-ol ( Example 28 , step 3 ) and 3-methyl-2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS # 2557358-38-8 ) to start preparation. Example 52 : 2-[2-[[(3 R )-1-(2- hydroxyethyl )-3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridin -5- yl ] -3- Methyl -5-( trifluoromethyl ) phenol

step 1 : N -[(3 R )-1-(2- Hydroxyethyl )-3- piperidinyl ] Tertiary butyl carbamate

The title compound was obtained as a pale yellow oil, LCMS: m/z 245.1 [M+H] ⁺ , ESI pos, which was obtained from N -[( 3R )-3- Tri -butyl piperidinyl]carbamate (CAS # 309956-78-3) and 2-iodoethanol (CAS # 624-76-0) were prepared initially.

step 2 : 2-[(3 R )-3-[(5- Chlorazolo [4,5- b ] pyridine -2- base ) Amino ]-1- piperidinyl ] ethanol

To tertiary -butyl N -[( 3R )-1-(2-hydroxyethyl)-3-piperidinyl] carbamate ( Example 52 , Step 1 ) (321 mg, 1.25 mmol, 1.12 eq) in 2 To a solution in methyl chloride (3.2 mL) and methanol (1.6 mL) was added dropwise 4 M HCl in dioxane (3.6 g, 3.0 mL, 12 mmol, 11.5 eq). Stir at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was taken up in 1,4-dioxane (2.0 mL) and 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92- 2, 220 mg, 1.04 mmol, 1.00 eq) and triethylamine (421 mg, 0.580 mL, 4.16 mmol, 4.00 eq). The light brown suspension was stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated aqueous NaHCO ₃ . The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 10% methanol in DCM) to afford the title compound (211 mg, yield 65 %). LCMS: m/z 297.1 [M+H] ⁺ , ESI pos.

step 3 : 2-[2-[[(3 R )-1-(2- Hydroxyethyl )-3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

The title compound was obtained as an off-white powder, LCMS: m/z 437.2 [M+H] ⁺ , ESI pos, from 2-[( 3R )-3-[ (5-Chlorazolo[4,5- b ]pyridin-2-yl)amino]-1-piperidinyl]ethanol ( Example 52 , step 2 ) and 3-methyl-2-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS # 2557358-38-8) The preparation was started. Example 53 : 2-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridin - 5- yl ]-3- fluoro- 5-( Trifluoromethyl ) phenol

step 1 : 2- bromine -6- fluorine -4-( Trifluoromethyl ) aniline

To a solution of 2-fluoro-4-trifluorotoluidine (CAS # 69409-98-9, 25.0 g, 140 mmol, 1.00 eq) in DMF (300 mL) was added NBS (26.1 g, 147 mmol, 1.05 eq). The mixture was stirred at 25°C for 12 hours. EtOAc (500 mL) was added to the reaction, washed with brine (500 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 1/0 to 10/1) to give the title compound (36.0 g, quantitative yield) as a yellow oil. LCMS: m/z 257.9 [M+H]+, ESI pos.

step 2 : 2- fluorine -6-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base )-4-( Trifluoromethyl ) aniline

To the _above solution of 2-bromo-6-fluoro-4-(trifluoromethyl)aniline (30.0 g, 116 mmol, 1.00 eq) in dioxane (500 mL) was added 4,4, 5,5-Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxo Borane (59.1 g, 233 mmol, 2.00 eq), KOAc (28.5 g, 291 mmol, 2.50 eq) and Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (9.50 g, 11.6 mmol, 0.10 eq). The mixture was stirred at 100°C for 3 hours. Upon completion, the reaction mixture was concentrated in vacuo. The residue was added to EtOAc (1000 mL), washed with brine (1000 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The reaction was worked up with additional material to give the title compound (45.0 g, crude) as a black oil which was used directly in the next step. LCMS: m/z 306.1 [M+H]+, ESI pos.

step 3 : 2- Amino -3- fluorine -5-( Trifluoromethyl ) phenol

To the above 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl ) to a solution of aniline (45.0 g, 148 mmol, 1.00 eq) in THF (600 mL) was added NaOH (2.00 M, 221 mL, 3.00 eq) and H ₂ O ₂ (100 g, 885 mmol, 85.0 mL, purity 30.0%, 6.00 eq), and the reaction was stirred at 25°C for 3 hours. After completion, EtOAc (1500 mL) was added to the reaction, washed with aqueous _Na2SO3 (1500 mL x 3), dried over _{Na2SO4 , filtered} and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (0.1% FA condition) to afford the title compound (11.0 g, 38% yield) as a brown solid. LCMS: m/z 196.0 [M+H]+, ESI pos.

step 4 : 3- fluorine -2- iodine -5-( Trifluoromethyl ) phenol

To the above 2-amino-3-fluoro-5-(trifluoromethyl)phenol (11.0 g, 56.4 mmol, 1.00 eq) and H ₂ SO ₄ (40.5 g, 404 mmol, 22.0 mL, purity 98.0 %, 7.17 eq) to a solution in H2O (200 mL) and acetone (50.0 mL) was added NaNO ₂ (7.78 g, 113 mmol, 2.00 eq) and the reaction was stirred at 0°C for 30 minutes. CuI (26.8 g, 141 mmol, 2.50 eq) and NaI (21.1 g, 141 mmol, 2.50 eq) were then added to the reaction at 0°C, and the reaction was stirred at 0°C for 1.5 hours. After completion, water (500 mL) was added to the reaction, washed with EtOAc (300 mL x 2). The combined organic layers were washed with brine (300 mL x 2), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 1/0 to 10/1) to give the title compound (20.0 g, crude product) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.04 (s, 1H), 6.89 (dd, 1H), 6.76 (s, 1H).

step 5 : 1-( Ethoxymethoxy )-3- fluorine -2- iodine -5-( Trifluoromethyl ) benzene

To the above 3-fluoro-2-iodo-5-(trifluoromethyl)phenol (20.0 g, 65.4 mmol, 1.00 eq) and chloromethoxyethane (9.09 mL, 98.0 mmol, 1.50 eq) in DMF (200 mL ) was added Cs ₂ CO ₃ (31.9 g, 98.0 mmol, 1.50 eq) and the mixture was stirred at 25°C for 2 hours. Upon completion, EtOAc (500 mL) was added to the reaction, washed with brine (500 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1/0 to 10/1) to obtain the title compound (10.0 g, yield 42%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.15 (s, 1H), 7.00 (dd, 1H), 5.36 (s, 2H), 3.78 (q, 2H), 1.24 (t, 3H).

step 6 : 2-[2-( Ethoxymethoxy )-6- fluorine -4-( Trifluoromethyl ) Phenyl ]-4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane

To the above 1-(ethoxymethoxy)-3-fluoro-2-iodo-5-(trifluoromethyl)benzene (10.0 g, 27.5 mmol, 1.00 eq) and 2-isopropoxy at -70°C In a solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15.3 g, 82.4 mmol, 16.8 mL, 3.00 eq) in THF (100 mL) n-BuLi (2.50 M, 27.5 mL, 2.50 eq) was added and the reaction was stirred at -70 °C for 1 h. After completion, aqueous NH ₄ Cl (300 mL) was added to the reaction, stirred for 10 min, and extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was subjected to preparative HPLC (column: Welch Ultimate XB-CN 250 × 50 × 10 um; mobile phase: [hexane-EtOH]; B%: 0%-0%, 7 minutes) to obtain white The title compound as a solid (7.00 g, 60% yield, 86.3% purity). ¹ H NMR (400 MHz, CDCl ₃ ): δ = 7.10 (s, 1H), 6.94 (d, 1H), 5.24 (s, 2H), 3.73 (q, 2H), 1.39 (s, 12H), 1.22 ( t, 3H).

step 7 : 5-[2-( Ethoxymethoxy )-6- fluorine -4-( Trifluoromethyl ) Phenyl ]- N -[(3 R )-1- Ethyl -3- piperidinyl ] zozolo [4,5- b ] pyridine -2- amine

5-Chloro- N -[( 3R )-1-ethyl-3-piperidinyl]oxazolo[4,5- b ]pyridin-2-amine ( Example 14 , Step 1) (70 mg, 0.24 mmol, 1.00 eq), the above 2-[2-(ethoxymethoxy)-6-fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl- 1,3,2-Dioxaborolane (201 mg, 0.47 mmol, 2.00 eq), potassium carbonate (131 mg, 0.95 mmol, 4.00 eq) and SPhos-Pd-G3 (CAS # 1445085-82-4 , 25 mg, 0.03 mmol, 0.14 eq) in 1,4-dioxane (2.8 mL) and water (0.70 mL) was flushed with argon and stirred at 110°C for 1 hour. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 10% methanol in DCM) to give the title compound as a brown oil (92 mg, yielding rate of 76%). LCMS: m/z 483.3 [M+H] ⁺ , ESI pos.

step 8 : 2-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-3- fluorine -5-( Trifluoromethyl ) phenol

To 5-[2-(ethoxymethoxy)-6-fluoro-4-(trifluoromethyl)phenyl] -N -[(3 R )-1-ethyl-3-piperene at 0°C To a solution of pyridyl]oxazolo[4,5- b ]pyridin-2-amine ( Example 53 , Step 1) (82 mg, 0.16 mmol, 1.00 eq) in DCM (2.1 mL) was added dropwise trifluoro Acetic acid (607 mg, 0.410 mL, 5.32 mmol, 33.0 eq). Stir at 0°C for 1.5 hours and at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was diluted with DCM and extracted with saturated NaHCO ₃ solution. The organic layer was washed with water and brine. The organic layer was back extracted twice with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 50% in DCM (DCM:methanol: _NH4OH 9:1:0.05)). All fractions containing product were combined and concentrated. The residue was triturated with ethyl acetate/heptane to afford the title compound (38 mg, 53% yield) as an off-white powder. LCMS: m/z 425.2 [M+H] ⁺ , ESI pos. Example 54 : 5- Chloro -2-[2-[[(3 R ,5 S )-1- ethyl -5- fluoro -3- piperidinyl ] amino ] oxazolo [4,5- b ] Pyridin -5- yl ]-3- methyl - phenol

step 1 : N -[( 3R ,5 S )-1- Ethyl -5- fluorine -3- piperidinyl ] Tertiary butyl carbamate

The title compound was obtained as an off-white solid, LCMS: m/z 247.1 [M+H] ⁺ , ESI pos, from N -[( 3R , 5S )- The preparation started with tert-butyl 5-fluoro-3-piperidinyl]carbamate (CAS # 1363378-08-8) and ethyl iodide (CAS # 75-03-6).

step 2 : (3 R ,5 S )-1- Ethyl -5- fluorine - piperidine -3- Amine hydrochloride

The title compound was obtained as an off-white foam, LCMS: m/z 147.1 [M+H] ⁺ , ESI pos, from N -[( 3R , 5S )-1 using chemistry similar to that described in step 2 of Example 46 -Ethyl-5-fluoro-3-piperidinyl]carbamate tert-butyl ester ( Example 54 , Step 1 ) was started.

step 3 : 5- chlorine - N -[(3 R ,5 S )-1- Ethyl -5- fluorine -3- piperidinyl ] zozolo [4,5- b ] pyridine -2- amine

The title compound was obtained as a yellow oil, LCMS: m/z 299.2 [M+H] ⁺ , ESI pos, from 5-chloro-2-(methylthio) using chemistry similar to that described in Example 46, step 3 Zazolo[4,5- b ]pyridine (CAS # 1783370-92-2) and (3 R ,5 S )-1-ethyl-5-fluoro-piperidin-3-amine hydrochloride ( Example 54 , step 2 ) Start the preparation.

step 4 : 5- chlorine -2-[2-[[(3 R ,5 S )-1- Ethyl -5- fluorine -3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl - phenol

The title compound was obtained as an off-white foam, LCMS: m/z 405.2 [M+H] ⁺ , ESI pos, from 5-chloro- N -[( 3R , 5S using chemistry similar to that described in Example 19) )-1-ethyl-5-fluoro-3-piperidinyl]oxazolo[4,5- b ]pyridin-2-amine ( Example 54 , step 3 ) and (4-chloro-2-hydroxyl-6 -Methyl-phenyl)boronic acid ( CAS# 1207961-50-9 ) was prepared initially. Example 55 : 2-[2-[[( 1R , 2R )-2-( dimethylamino ) cyclopropyl ] amino ] oxazolo [4,5- b ] pyridin - 5- yl ] -3- Methyl -5-( trifluoromethyl ) phenol

step 1 : N -[( 1R ,2 R )-2-[(5- Chlorazolo [4,5- b ] pyridine -2- base ) Amino ] Cyclopropyl ] Tertiary butyl carbamate

To 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 180 mg, 0.85 mmol, 1.00 eq) in 1,4-dioxane ( 2.0 mL) was sequentially added N -[(1 R ,2 R )-2-aminocyclopropyl]carbamic acid tertiary butyl ester (CAS # 1332761-28-0, 155 mg, 0.90 mmol, 1.06 eq) and triethylamine (102 mg, 0.14 mL, 1.00 mmol, 1.18 eq). The reaction mixture was stirred at 90°C for 5 hours and at 100°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated NaHCO ₃ solution. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 70% ethyl acetate in heptane) to afford the title compound (200 mg, yield 69%). LCMS: m/z 325.1 [M+H] ⁺ , ESI pos.

step 2 : N -[(1 R ,2 R )-2-[[5-[2- hydroxyl -6- methyl -4-( Trifluoromethyl ) Phenyl ] zozolo [4,5- b ] pyridine -2- base ] Amino ] Cyclopropyl ] Tertiary butyl carbamate

The title compound was obtained as a pale yellow foam, LCMS: m/z 465.4 [M+H] ⁺ , ESI pos, from N -[( 1R , 2R )- 2-[(5-Chlorozozolo[4,5- b ]pyridin-2-yl)amino]cyclopropyl]carbamic acid tertiary butyl ester ( Example 55 , step 1 ) and 3-methyl-2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS # 2557358-38-8 ) to start preparation.

step 3 : 2-[2-[[(1 R ,2 R )-2- Aminocyclopropyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

N -[(1 R ,2 R )-2-[[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5- b ]pyridin-2-yl]amino]cyclopropyl]carbamate tert-butyl ester ( Example 55 , Step 2 ) (193 mg, 0.39 mmol, 1.00 eq) in DCM (1.0 mL) and methanol (0.50 mL) To the solution in 4 M HCl in dioxane (0.88 mL, 3.52 mmol, 8.92 eq) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, and the residue was extracted with DCM/methanol (19:1) and saturated aqueous NaHCO ₃ containing a few drops of water. The aqueous layer was back extracted twice with DCM/methanol (19:1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 100% in DCM (DCM:methanol: _NH4OH 9:1:0.05)) to give The title compound (92 mg, 61% yield) as an off-white solid. LCMS: m/z 365.1 [M+H] ⁺ , ESI pos.

step 4 : 2-[2-[[(1 R ,2 R )-2-( Dimethylamino ) Cyclopropyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

To 2-[2-[[(1 R ,2 R )-2-aminocyclopropyl]amino]oxazolo[4,5- b ]pyridin-5-yl]-3-methyl-5 -(Trifluoromethyl)phenol ( Example 55 , Step 3 ) (74 mg, 0.20 mmol, 1.00 eq) To a mixture in 1,2-dichloroethane (2.0 mL) was added 37% aqueous formaldehyde (33 mg , 0.03 mL, 0.40 mmol, 1.98 eq), then sodium triacetyloxyborohydride (180 mg, 0.85 mmol, 4.18 eq) was added in portions. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was extracted with saturated aqueous NaHCO ₃ and three times with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 10% methanol in DCM). All fractions containing product were combined and concentrated in vacuo. The residue was taken up on ISOLUTE HM-N and flash-chromatographed (SI-amine, gradient: 0% to 10% methanol in ethyl acetate) to give the title compound (31 mg, yield rate 37%). LCMS: m/z 393.2 [M+H] ⁺ , ESI pos. Example 56 : 3- Hydroxy -4-[2-[[(3 R ,5 S )-5- hydroxy -1- methyl -3- piperidinyl ] amino ] oxazolo [4,5- b ] Pyridin -5- yl ]-5- methyl - benzonitrile

The title compound was obtained as an off-white powder, LCMS: m/z 380.2 [M+H] ⁺ , ESI pos, from ( 3S , 5R )-5-[(5 -Chlorozozolo[4,5- b ]pyridin-2-yl)amino]-1-methyl-piperidin-3-ol ( Example 49 , step 3 ) and (4-cyano-2-hydroxyl -6-Methyl-phenyl)boronic acid ( Example 25 , Step D ) The preparation was started. Examples 57 and 58 : cis -2-[2-[(3- hydroxy -3- methyl - cyclobutyl ) methylamino ] oxazolo [4,5-b] pyridin -5- yl ]- 3- methyl -5-( trifluoromethyl ) phenol and trans -2-[2-[(3- hydroxy -3- methyl - cyclobutyl ) methylamino ] oxazolo [4,5 -b] pyridin -5- yl ]-3- methyl -5-( trifluoromethyl ) phenol

step 1 : N -[(3- hydroxyl -3- methyl - Cyclobutyl ) methyl ] Tertiary butyl carbamate

Add tertiary-butyl N -[(3-oxocyclobutyl)methyl]carbamate (CAS # 130369-09-4, 400 mg, 2.01 mmol, 1.00 eq) in tetrahydrofuran (14 mL) at 0°C A solution of 3.2 M methylmagnesium bromide in 2-methyltetrahydrofuran (CAS #75-16-1, 1.4 mL, 4.48 mmol, 2.23 eq) was added dropwise to the solution. After stirring at 0°C for 3 hours, a solution of 3.2 M methylmagnesium bromide in 2-methyltetrahydrofuran (CAS #75-16-1, 0.700 mL, 2.24 mmol, 1.12 eq) was added dropwise at 0°C. Stir at 0°C for 15 minutes and at room temperature for 15 minutes. The reaction mixture was cooled to 0 °C, quenched by dropwise addition of saturated aqueous _NH4Cl , and then extracted with ethyl acetate. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was absorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient: 0% to 60% ethyl acetate in heptane) to give the title compound (334 mg, yield 70%, purity 90%). LCMS: m/z 160.1 [M-tBu+H] ⁺ , ESI pos.

step 2 : 3-[[(5- Chlorazolo [4,5- b ] pyridine -2- base ) Amino ] methyl ]-1- methyl - Cyclobutanol

To tert -butyl N -[(3-hydroxy-3-methyl-cyclobutyl)methyl]carbamate ( Example 57 , Step 1 ) (116 mg, 0.48 mmol, 1.22 eq, 90% purity) in DCM (1.2 mL) and a solution in methanol (0.60 mL) was added dropwise 4 M HCl in dioxane (1.39 g, 1.16 mL, 4.63 mmol, 11.6 eq). Stir at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was taken up in 1,4-dioxane (0.80 mL) and 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92- 2, 80 mg, 0.40 mmol, 1.00 eq) and triethylamine (128 mg, 0.176 mL, 1.26 mmol, 3.17 eq). The brown suspension was stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated aqueous NaHCO ₃ . The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 5% methanol in DCM) to give the title compound as an off-white foam (94 mg, yielding 79% yield, 90% yield). LCMS: m/z 268.3 [M+H] ⁺ , ESI pos.

step 3 : cis -2-[2-[(3- hydroxyl -3- methyl - Cyclobutyl ) Methylamino ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) Phenol and trans -2-[2-[(3- hydroxyl -3- methyl - Cyclobutyl ) Methylamino ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

3-[[(5-Chloroxazolo[4,5- b ]pyridin-2-yl)amino]methyl]-1-methyl-cyclobutanol ( Example 57 , step 2 ) (92 mg , 0.31 mmol, 1.00 eq), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-( Trifluoromethyl)phenol (CAS # 2557358-38-8, 131 mg, 0.43 mmol, 1.40 eq), cesium carbonate (290 mg, 0.89 mmol, 2.88 eq) and XPhos Pd G3 (27 mg, 0.03 mmol, 0.10 eq ) in 1,4-dioxane (1.2 mL) and water (0.30 mL) was flushed with argon and stirred at 100°C for 1 hour, then cooled in a hot oil bath with stirring for 16 hours. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 10% methanol in DCM). All fractions containing product were combined and concentrated in vacuo. The residue was further purified by SFC (column: chiral IC, eluent B: 15% methanol + 0.2% diethylamine) to separate the cis/trans mixture to give cis -2- [2-[(3-Hydroxy-3-methyl-cyclobutyl)methylamino]oxazolo[4,5- b ]pyridin-5-yl]-3-methyl-5-(trifluoro Methyl)phenol (66 mg, 47% yield, 90% purity) (eluted first, retention time = 2.11 min), LCMS: m/z 408.3 [M+H] ⁺ , ESI pos; and light brown foam trans -2-[2-[(3-Hydroxy-3-methyl-cyclobutyl)methylamino]oxazolo[4,5- b ]pyridin-5-yl]-3-methyl- 5-(Trifluoromethyl)phenol (33 mg, 24% yield, 90% purity) (2nd eluate, retention time = 2.89 min), LCMS: m/z 408.3 [M+H] ⁺ . Example 59 : 5- Chloro -2-[2-[(1- ethyltetrahydroazil- 3- yl ) methylamino ] oxazolo [4,5- b ] pyridin -5- yl ]-3 -Methyl - phenol _

step A : 3-[[(5- Chlorazolo [4,5-b] pyridine -2- base ) Amino ] methyl ] Tetrahydroacridine -1- Tertiary butyl formate

According to GP1 , 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (150 mg, 0.710 mmol), 3-(aminomethyl)tetrahydroazolo-1-carboxylic acid Tertiary butyl ester (CAS # 325775-44-8, 143 µL, 0.785 mmol), Et ₃ N (111 µL, 0.796 mmol) in dioxane (1.5 mL) was stirred overnight at 90°C. After work-up and purification by flash chromatography (silica gel, EtOAc, heptane 0% to 70% ethyl acetate), the title compound was obtained as a pale yellow solid (168 mg, 70%). LC-MS: m/z 337.1 [MH] ^- , ESI neg.

step B : N -( Tetrahydroacridine -3- methyl group )-5- chlorine - zozolo [4,5-b] pyridine -2- amine; 2,2,2- Trifluoroacetate

According to GP3 , the above-mentioned tertiary butyl 3-[[(5-chloroazolo[4,5-b]pyridin-2-yl)amino]methyl]tetrahydroazia-1- carboxylate ( Example 59 , Step A ) (166 mg, 0.490 mmol) and TFA (340 µL, 4.41 mmol) in DCM (3.58 mL) were stirred at room temperature for 30 min to afford the title compound (320 mg, 93%) as a pale yellow oil. LC-MS: m/z 239.1 [M+H] ⁺ , ESI pos.

step C : 5- chlorine - N -[(1- Ethyltetrahydroacridine -3- base ) methyl ] zozolo [4,5-b] pyridine -2- amine

According to GP4 , the above-mentioned N- (tetrahydroazia-3-ylmethyl)-5-chloro-oxazolo[4,5-b]pyridin-2-amine; 2,2,2-trifluoroacetic acid ( Example 59 , step B ) (320 mg, 0.454 mmol), acetaldehyde (46 µL, 0.926 mmol), sodium acetate (74.5 mg, 0.908 mmol), sodium triacetyloxyborohydride (144 mg, 0.60 mmol) in DCM (0.965 mL) and methanol (0.965 mL) were stirred at 0°C. The reaction mixture was stirred at 0 °C for 30 minutes and at room temperature for 30 minutes. After work-up, the crude product was taken up on silica gel and purified by flash chromatography (TELOS Flash _NH2 , 10 g, gradient: 0% to 20% methanol in DCM) to afford the title as a pale yellow solid compound (97 mg, 7%). LC-MS: m/z 267.2 [M+H] ⁺ , ESI pos.

step D. : 5- chlorine -2-[2-[(1- Ethyltetrahydroacridine -3- base ) Methylamino ] zozolo [4,5-b] pyridine -5- base ]-3- methyl - phenol

According to GP2a , the above (5-chloroazolo[4,5-b]pyridin-2-yl)-[(1-ethyltetrahydroacrin-3-yl)methyl]amine ( Example 59 , step C ) (95 mg, 0.321 mmol), (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (CAS # 1207961-50-9, 102 mg, 0.549 mmol), potassium carbonate (213 mg, 1.54 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride(ii) DCM complex (39.8 mg, 0.049 mmol) in 1,4-dioxane (1.99 mL) and water (1 mL) at 95°C overnight. After work-up, the crude product was absorbed on ISOLUTE HM-N and purified first by flash chromatography (silica gel, gradient: 0% to 10% methanol in DCM) and then by RP HPLC (C ₁₈ , YMC -Triart, 12 nm, 5 µm, 100 × 30 mm, ACN/water+0.1% TEA) to afford the title compound (35 mg, 26%) as an off-white solid after lyophilization. LC-MS: m/z 371.1 [MH] ^- , ESI neg. Example 60 : 1-[5-(4- Chloro -2- hydroxyl -6- methyl - phenyl )-2-[[ rac- (3R)-1- methyl -3- piperidinyl ] amine Base ] oxazolo [4,5-b] pyridin -7- yl ] pyrrolidin -2- one

step A : 6- chlorine -4- iodine -2- Nitropyridine -3- alcohol

The device was dried by heating with an air heater under vacuum. In a three-neck round-bottom flask, dissolve 6-chloro-4-iodopyridin-3-ol (CAS # 877133-58-9, 10.0 g, 39.2 mmol, 1.0 eq) in acetic acid (100 mL) at 0 °C Fuming nitric acid (6.17 g, 97.9 mmol, 2.5 eq) was added and the mixture was stirred at 25 °C for 12 hours. After cooling to ambient temperature, the reaction mixture was quenched with ice-water (20 mL), then extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=2:1 to 1:1) to give the title compound (2.0 g, yield 17%) as a yellow solid. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.40 (s, 1H).

step B : 2- Amino -6- chlorine -4- Iodopyridine -3- alcohol

To the above mixture of 6-chloro-4-iodo-2-nitropyridin-3-ol (2.0 g, 6.66 mmol, 1.0 eq) in methanol (30 mL) was added tin(ll) chloride (6.31 g, 33.3 mmol, 5.0 eq), and the mixture was stirred at 70°C for 2 hours. After cooling to ambient temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1 to 1:1) to obtain the title compound (1.80 g, yield 99%) as a yellow solid. LCMS: m/z 270.9 [M+H] ⁺ , ESI pos.

step C : 5- chlorine -7- Iodozozolo [4,5-b] pyridine -2- Thiol

The device was dried by heating with an air heater under vacuum. To a mixture of 2-amino-6-chloro-4-iodopyridin-3-ol (2000.0 mg, 7.39 mmol, 1.0 eq) in DMF (50 mL) was added TCDI (2632.55 mg, 14.79 mmol, 2.0 eq) , and the mixture was stirred at 50°C for 12 hours. After cooling to ambient temperature, the reaction mixture was quenched with water (20 mL), then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1000 mg, 43% yield) as a yellow solid. LCMS: m/z 312.8 [M+H] ⁺ , ESI pos.

step D. : 2,5- Dichloro -7- Iodozozolo [4,5- b ] pyridine and 5- chlorine -7- iodine -2-( Methylthio ) zozolo [4,5- b ] pyridine

To 5-chloro-7-iodozozolo[4,5-b]pyridine-2-thiol (1000.0 mg, 3.2 mmol, 1.0 eq) in oxalyl chloride (20307.5 mg, 160 mmol, 50.0 eq) To the mixture was added DMF (23.4 mg, 0.32 mmol, 0.1 eq), and the mixture was stirred at 60 °C for 1 hr. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 1:1) to obtain 2,5-dichloro-7-iodooxazolo[4,5 -b]pyridine (140 mg, yield 14%) and 5-chloro-7-iodo-2-(methylthio)oxazolo[4,5-b]pyridine (430 mg, yield 41%) as yellow solid %). LCMS: m/z 326.8 [M+H] ⁺ , ESI pos.

step E. : ( R )-5- chlorine -7- iodine - N -(1- Methylpiperidine -3- base ) zozolo [4,5-b] pyridine -2- amine

To a mixture of (R)-1-methylpiperidin-3-amine (601.5 mg, 5.27 mmol, 4.0 eq) in NMP (5 mL) was added 5-chloro-7-iodo-2-(methylthio ) oxazolo[4,5-b]pyridine (430 mg, 1.32 mmol, 1.0 eq) and DIEA (339.7 mg, 2.63 mmol, 2.0 eq), and the mixture was stirred at 25°C for 2 hours. The reaction mixture (combined with another batch of 0.14 g) was quenched with water (1 mL), then diluted with MeOH (3 mL). The mixture was purified by column chromatography (C ₁₈ , 0.1% TFA water/ACN conditions), then the desired fractions were combined and lyophilized to give the title compound (550 mg, 106% yield) as a yellow solid. LCMS: m/z 393.0 [M+H] ⁺ , ESI pos.

step f : ( R )-1-(5- chlorine -2-((1- Methylpiperidine -3- base ) Amino ) zozolo [4,5-b] pyridine -7- base ) Pyrrolidine -2- ketone

To the above (R)-5-chloro-7-iodo-N-(1-methylpiperidin-3-yl)oxazolo[4,5-b]pyridin-2-amine ( Example 60 , Step E ) (350 mg, 0.89 mmol, 1.0 eq) and pyrrolidin-2-one (0.54 mL, 7.13 mmol, 8.0 eq) in 1,4-dioxane (5 mL) was added N,N -dimethyl Base-1,2-ethylenediamine (7.86 mg, 0.09 mmol, 0.1 eq), K ₂ CO ₃ (307.55 mg, 2.23 mmol, 2.5 eq) and CuI (16.9 mg, 0.09 mmol, 0.10 eq), and the mixture Stir at 120 °C for 12 h under _N2 . After cooling to ambient temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (C ₁₈ , 0.1% TFA in water/MeCN), then the desired fractions were combined and lyophilized to give the title compound as a yellow solid (50.0 mg, 16% yield ). LCMS: m/z 350.0 [M+H] ⁺ , ESI pos.

step G : 1-[5-(4- chlorine -2- hydroxyl -6- methyl - Phenyl )-2-[[ Racemization -(3R)-1- methyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -7- base ] Pyrrolidine -2- ketone

The device was dried by heating with an air heater under vacuum. To the above (R)-1-(5-chloro-2-((1-methylpiperidin-3-yl)amino)oxazolo[4,5-b]pyridin-7-yl) at 25°C Pyrrolidin-2-one (10.0 mg, 0.03 mmol, 1.00 eq), Pd(dppf)Cl ₂ (2.09 mg, 0.10 eq) and (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid ( CAS # 1207961-50-9, 5.33 mg, 0.03 mmol, 1.00 eq) To a mixture of 1,4-dioxane (1 mL) and water (0.2 mL) was added CsF (13.03 mg, 0.09 mmol, 3.0 eq ), and the mixture was stirred at 120 °C for 2 h under microwave. After cooling to ambient temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (C ₁₈ , 0.1% TFA in water/MeCN), then the desired fractions were combined and lyophilized to give the title compound as a yellow solid (3.8 mg, 23% yield ). LC-MS (using SHIMADZU LCMS-2020, Agilent 1200 LC/G1956A MSD and Agilent 1200\G6110A, Agilent 1200 LC and Agilent 6110 MSD. Mobile phase: A: 0.038% TFA in water (v/v); B: 0.019 % TFA in acetonitrile (v/v. Column: Kinetex EVO C18 2.1 × 30 mm, 5 μm). LCMS: m/z 456.1 [M+H] ⁺ ESI pos. Example 61 : 2-[2-[[(3 R )-1-(3- hydroxycyclobutyl )-3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridin -5- yl ]-3- methyl -5-( trifluoromethyl ) phenol

step A : (3R)-3-[(5- Chlorazolo [4,5-b] pyridine -2- base ) Amino ] piperidine -1- Tertiary butyl formate

To 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS # 1783370-92-2, 0.60 g, 2.84 mmol, 1.00 eq) in 1,4-dioxane ( (3 R )-3-aminopiperidine-1-carboxylic acid tertiary butyl ester (CAS # 188111-79-7, 629 mg, 3.14 mmol, 1.11 eq) and triethylamine were added sequentially to the solution in 6 mL) (444 µL, 3.19 mmol, 1.121 eq). The brown solution was stirred overnight at 90 °C. (3R)-tert-butyl 3-aminopiperidine-1-carboxylate (631.5 mg, 3.15 mmol, 1.110 eq) was added to the reaction mixture and it was stirred for another two hours and finally overnight at 90°C. Additional (3R)-3-aminopiperidine-1-carboxylic acid tert- butyl ester (284 mg, 1.42 mmol, 0.50 eq) and triethylamine (222 µL, 1.59 mmol, 0.56 eq) were added to the reaction mixture , and stirred for another 1 hour. After the reaction was completed, the reaction mixture was cooled to room temperature, and extracted with about 60 mL of ethyl acetate and about 15 mL of saturated NaHCO ₃ solution. The aqueous layer was back extracted with about 50 mL of ethyl acetate. The organic layer was washed with about 15 mL of water and about 15 mL of brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, DCM/MeOH 0% to 10% MeOH) to afford the title compound (1.00 g, 95%) as a yellow solid. LCMS: m/z 351.1 [MH] ^- , ESI neg.

step B : 5- chlorine - N -[(3 R )-3- piperidinyl ] zozolo [4,5-b] pyridine -2- Amine; hydrochloride

The above-mentioned (3 R )-3-[(5-chloroazolo[4,5-b]pyridin-2-yl)amino]piperidine-1-carboxylic acid tertiary butyl ester (1.17 g, 3.32 mmol, 1.00 eq) was dissolved in extra-dry DCM (12.2 mL) and methanol (6.07 mL). Under ice-bath cooling, 4 M HCl in dioxane (8.04 mL, 32.2 mmol, 9.70 eq) was added slowly. After addition of HCl, the ice bath was removed. The reaction was stirred at room temperature for 3 hours. The solvent was evaporated to give the title compound as a yellow solid as the 1:1 hydrochloride salt without further purification (1.09 g, 91% yield, 80% purity). LCMS: m/z 253.1 [M+H] ⁺ , ESI pos.

step C : 3-[(3 R )-3-[(5- Chlorazolo [4,5-b] pyridine -2- base ) Amino ]-1- piperidinyl ] Cyclobutanol

The above 5-chloro-N-[(3R)-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine; hydrochloride (100 mg, 346 µmol, 1.00 eq) was suspended in DCM (3 mL), and added 3-hydroxycyclobutan-1-one (30.7 mg, 345.8 µmol, 1.00 eq) at 0°C. The mixture was stirred at 0 °C for 1.5 h, then allowed to warm to room temperature. Then sodium triacetyloxyborohydride (147 mg, 692 µmol, 2.00 eq) and acetic acid (39.6 µL, 692 µmol, 2.00 eq) were added sequentially. The suspension was stirred overnight at room temperature. The reaction mixture was diluted with saturated NaHCO ₃ solution and extracted twice with EtOAc. _The organic layer was washed with water and brine, dried over _Na2SO4 , and concentrated to dryness. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 10% MeOH+0.02% _NH4OH in DCM) to give the title compound as an orange viscous oil (32 mg, 27% yield). LCMS: m/z 323.2; 325.1 (Cl isotope) [M+H]+, ESI pos.

step D. : 2-[2-[[(3 R )-1-(3- Hydroxycyclobutyl )-3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

According to GP2 , the above-mentioned 3-[(3R)-3-[(5-chloroazolo[4,5-b]pyridin-2-yl)amino]-1-piperidinyl]cyclobutanol (32 mg, 0.099 mmol, 1.00 eq), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- (Trifluoromethyl)phenol (CAS # 2557358-38-8, 44.9 mg, 149 µmol, 1.50 eq), cesium carbonate (96.9 mg, 297 µmol, 3.00 eq) and xphos-pd-g3 gt (8.39 mg, 9.91 umol, 0.100 eq) was stirred in 1,4-dioxane (0.5 mL) and water (0.125 mL) at 90°C overnight. After work-up, the crude product was absorbed on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 10% DCM/MeOH+0.02% _NH4OH ) to give 117 mg The title compound, but it contained an unknown impurity, was therefore purified by RP-HPLC (column: YMC-Triart C ₁₈ , 12 nm, 5 µm, 100 × 30 mm; 56% to 50% ACN/water + 0.1% HCOOH). Further purification to finally afford the title compound (6 mg, 13% yield) as a white solid. LCMS: m/z 461.3 [M+H] ⁺ , ESI pos. Example 62 : 2-[2-(1,3,3a,4,6,6a- hexahydrofuro [ 3,4-c] pyrrol -5- yl ) oxazolo [4,5-b] pyridine- 5- yl ]-3- methyl -5-( trifluoromethyl ) phenol

step A : 2-(1,3,3a,4,6,6a- Hexahydrofurano [3,4-c] pyrrole -5- base )-5- chlorine - zozolo [4,5-b] pyridine

According to GP1 , 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (80 mg, 0.399 mmol), 3,3a,4,5,6,6a-hexahydro-1 H -furo[3,4- c ]pyrrole (CAS # 60889-32-9, 0.441 mmol, 48.5 µL), triethylamine (62.2 µL, 0.447 mmol) in 1,4-dioxane ( 0.842 mL) and stirred overnight. After work-up and purification using column chromatography followed by HPLC, the title compound was obtained as a pale yellow solid (58 mg, 52%). LCMS: m/z 266.1 [M+H] ⁺ , ESI pos.

step B : 2-[2-(1,3,3a,4,6,6a- Hexahydrofurano [3,4-c] pyrrole -5- base ) zozolo [4,5-b] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

According to GP2b , the above 2-[2-[[(3R)-1-(3-hydroxycyclobutyl)-3-piperidinyl]amino]oxazolo[4,5-b]pyridine-5- base]-3-methyl-5-(trifluoromethyl)phenol (35.0 mg, 0.132 mmol) and [2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]boronic acid (CAS # 2557358-06-0, 42.1 mg, 0.191 mmol) in extra dry 1,4-dioxane (0.521 mL) and water (0.130 mL), cesium carbonate (123 mg, 0.379 mmol), XPhos Pd G3 (11.5 mg, 0.013 mmol) at 100°C for 1 hour. The title compound was obtained as a pale yellow solid (32 mg, 57%) after work-up and purification by flash chromatography (silica gel, EtOAC/heptane: 0% to 100% EtOAc). LCMS: m/z 406.4 [M+H] ⁺ , ESI pos. Example 63 : 5- Chloro -3- methyl -2-[2-[[(3 R )-1-( oxetan -3- yl )-3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridin -5- yl ] phenol

step A : 5- chlorine - N -[(3 R )-1-( Oxetane -3- base )-3- piperidinyl ] zozolo [4,5- b ] pyridine -2- amine

According to GP1 , 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 300 mg, 1.27 mmol), [(3R)-1-( Oxetan-3-yl)-3-piperidinyl]amine (CAS # 1349700-06-6, 220 mg, 1.41 mmol), triethylamine (213 µL, 1.53 mmol) in 1,4-di Oxane (3 mL) was stirred at 90°C overnight and at 100°C for another 4 hours. A precipitate formed which was triturated in ether and isolated as a light yellow solid (title compound) (315 mg, 63% yield, 85% purity). LCMS: m/z 309.2 [M+H] ⁺ , ESI pos.

step B : 5- chlorine -3- methyl -2-[2-[[(3R)-1-( Oxetane -3- base )-3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ] phenol

According to GP2a , the above 5-chloro-N-[(3R)-1-(oxetan-3-yl)-3-piperidinyl]oxazolo[4,5-b]pyridine-2- Amine (150 mg, 0.413 mmol), (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (CAS # 1207961-50-9, 131 mg, 0.702 mmol), potassium carbonate (257 mg, 1.86 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride DCM complex (50.6 mg, 0.062 mmol ) in 1,4-dioxane (3.4 mL) and water (1.7 mL) were stirred for 16 hours. After work-up and purification (on-column and trituration with ether/heptane) the title compound was obtained as a light brown powder (103 mg, 57%). LCMS: m/z 413.3; 415.2 (Cl isotope) [MH] ^- , ESI neg. Example 64 : 3- Methyl -2-[2-[ rac- (4aS,7aS)-3,4a,5,6,7,7a- hexahydro -2H- pyrrolo [3,4-b] [1,4] oxazin -4- yl ] oxazolo [4,5-b] pyridin -5- yl ]-5-( trifluoromethyl ) phenol; 2,2,2- trifluoroacetic acid and its Corresponding enantiomers 64a and 64b

step A : rel-(4aS,7aS)-4-(5- Chlorazolo [4,5-b] pyridine -2- base )-2,3,4a,5,7,7a- Hexahydropyrrolo [3,4-b][1,4] oxazine -6- Tertiary butyl formate

According to GP1 , 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (100 mg, 0.498 mmol), rel-(4aS,7aS)-3,4,4a,5, tertiary-butyl 7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxylate (CAS # 138026-93-4, 125 mg, 0.548 mmol), tri Ethylamine (56.5 mg, 77.8 µL, 0.558 mmol) was stirred in 1,4-dioxane (0.61 mL) at 90°C overnight. Additional tert-butyl 4-amino-2-azabicyclo[2.2.2]octane-2- carboxylate (124 mg, 0.548 mmol) and triethylamine (56.5 mg, 77.8 µL, 0.558 mmol) were added into the reaction mixture, which was stirred for six hours. The reaction was then stopped, and after work-up and purification, the title compound (84 mg, 44%) was obtained as an off-white solid. LCMS: m/z 381.1 [M+H] ⁺ , ESI pos.

step B : rel-(4aS,7aS)-4-[5-[2,6- Dimethyl -4-( Trifluoromethyl ) Phenyl ] zozolo [4,5-b] pyridine -2- base ]-2,3,4a,5,7,7a- Hexahydropyrrolo [3,4-b][1,4] oxazine -6- Tertiary butyl formate

According to GP2b , the above rel-(4aS,7aS)-4-(5-chloroazolo[4,5-b]pyridin-2-yl)-2,3,4a,5,7,7a-hexahydro Pyrrolo[3,4-b][1,4]oxazine-6-carboxylic acid tertiary butyl ester (82.0 mg, 0.215 mmol), 3-methyl-2-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (94.5 mg, 0.313 mmol), cesium carbonate (202 mg, 0.619 mmol), XPhos Pd G3 (18.8 mg, 0.021 mmol) was stirred in 1,4-dioxane (0.851 mL) and water (0.213 mL) at 100°C overnight. After work-up and purification, the title compound (75 mg, 67%) was obtained as a yellow solid. LCMS: m/z 521.3 [M+H] ⁺ , ESI pos.

step C : 3- methyl -2-[2-[ Racemization -(4aS,7aS)-3,4a,5,6,7,7a- Hexahydro -2H- pyrrolo [3,4-b][1,4] oxazine -4- base ] zozolo [4,5-b] pyridine -5- base ]-5-( Trifluoromethyl ) phenol; 2,2,2- Trifluoroacetic acid and its corresponding enantiomers 64a and 64b

According to GP3 , the above rel-(4aS,7aS)-4-[5-[2,6-dimethyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine- 2-yl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-6-carboxylic acid tertiary butyl ester (75.0 mg, 0.144 mmol) , TFA (167 µL, 2.16 mmol) was stirred in DCM (0.64 mL) at room temperature for 1 h to afford the title compound ( Example 64 ) (96 mg, 80% purity) as an orange solid. LCMS: m/z 419.2 [MH] ^- , ESI neg.

Racemate 64 was then separated using chiral HPLC (column: chiral IF, 5 µm, 250 × 20 mm; 35% MeOH + 0.2% DEA, SFC) to give two trans-enantiomers 64a ( 20 mg, 25%) and 64b (19 mg, 24%, both orange solids. LCMS: m/z 419.2 [MH] ⁻ , ESI neg. Example 65 : 2-[2-(1,2,3 ,5,6,7,8,8a -Swainson -6- ylamino ) oxazolo [4,5-b] pyridin -5- yl ]-5- chloro -3- methyl - phenol

step A : N -(1,2,3,5,6,7,8,8a- Swainsonine -6- base )-5- chlorine - zozolo [4,5-b] pyridine -2- amine

According to GP1 , 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (300 mg, 1.5 mmol), indolizin-6-ylamine (CAS # 1824202-77-8 , 226 µL, 1.66 mmol), triethylamine (233.4 µL, 1.67 mmol) were stirred in 1,4-dioxane (3.16 mL) at 90°C for 2 days. Stop responding. After work-up and purification using column chromatography, the title compound was obtained as a yellow solid (94 mg, 21%). LCMS: m/z 293.1 [M+H] ⁺ , ESI pos.

step B : 2-[2-(1,2,3,5,6,7,8,8a- Swainsonine -6- Amino ) zozolo [4,5-b] pyridine -5- base ]-5- chlorine -3- methyl - phenol

According to GP2a , the above N- (1,2,3,5,6,7,8,8a-swainson-6-yl)-5-chloro-oxazolo[4,5- b ]pyridine- 2-Amine (90 mg, 0.307 mmol), (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (CAS # 1207961-50-9, 98.1 mg, 0.526 mmol), potassium carbonate (204 mg , 1.48 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(ii) DCM complex (38.2 mg, 0.047 mmol) in 1,4-dioxane at 95℃ (1.91 mL) and water (0.954 mL) and stirred overnight. (4-Chloro-2-hydroxy-6-methyl-phenyl)boronic acid (CAS # 1207961-50-9, 45.8 mg, 0.246 mmol) and 1,1'-bis(diphenylphosphino)diocene Iron-palladium(ii) dichloride DCM complex (19.1 mg, 0.023 mmol) was added to the reaction mixture and it was stirred at 95°C for two hours. After work-up and two purifications (one column chromatography and HPLC), the title compound (19 mg, 15%) was obtained as a gray solid. LCMS: m/z 397.2 [M+H] ⁺ , ESI pos. Example 66 : 3- Methyl -2-[2-[(1- methyltetrahydroazil -2- yl ) methylamino ] oxazolo [4,5-b] pyridin -5- yl ]- 5-( Trifluoromethyl ) phenol and its enantiomers 66a and 66b.

step A : 5- chlorine - N -[(1- methyltetrahydroacridine -2- base ) methyl ] zozolo [4,5- b ] pyridine -2- amine

According to GP1 , 2-aminomethyl-1-methyltetrahydroacridine (102.5 mg, 0.972 mmol), 2-aminomethyl-1-methyltetrahydroacridine (102.5 mg, 0.972 mmol), Triethylamine (125 µL, 0.897 mmol) was stirred in 1,4-dioxane (1 mL) at 90°C overnight. After work-up and purification using column chromatography, the title compound was obtained as an off-white solid (104 mg, 55%). LCMS: m/z MS: 253.1; 255.0 [M+H] ⁺ , ESI pos.

step B : 3- methyl -2-[2-[[(2S)-1- methyltetrahydroacridine -2- base ] Methylamino ] zozolo [4,5-b] pyridine -5- base ]-5-( Trifluoromethyl ) Phenols and their corresponding enantiomers 66a and 66b

According to GP2b , the above (5-chloroazolo[4,5-b]pyridin-2-yl)-[(1-methyltetrahydroacrin-2-yl)methyl]amine (104 mg, 0.412 mmol), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl) Phenol (196.31 mg, 0.617 mmol), cesium carbonate (402.3 mg, 1.23 mmol) and xphos-pd-G3 (36.6 mg, 0.043 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.50 mL) was stirred overnight. Add 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol ( 98.2 mg, 0.309 mmol), xphos-pd-G3 (17.4 mg, 0.021 mmol) and cesium carbonate (201.14 mg, 0.617 mmol), and the mixture was stirred at 90°C for another day. After work-up and purification, the title compound ( Example 66 ) (67 mg, 41%) was obtained as a white powder. LCMS: m/z 391.3 [MH] ^- , ESI+.

33 mg of the title compound ( Example 66 ) were purified by chiral HPLC (column: Chiral IC, 5 µm, 100 x 4.6 mm; 20% to 40% MeOH+0.2% DEQ, SFC) to give two fractions (13 mg, 34%) and (12 mg, 37%), both as light brown solids. Example 67 : 5- chloro -2-[2-( 1H - imidazol -5- ylmethylamino ) oxazolo [4,5- b ] pyridin -5- yl ]-3- methyl - phenol; formic acid

step A : (5- Chlorazolo [4,5- b ] pyridine -2- base )-(1 H- imidazole -5- methyl group ) amine

1 H - imidazole- 5-ylmethylamine; hydrochloride (139 mg, 1.04 mmol, 2.2 eq) and triethylamine (178 mg, 245 µL, 1.76 mmol, 3.7 eq). The brown solution was stirred overnight at 130°C. 1 H -imidazol-5-ylmethylamine; hydrochloride (139 mg, 1.04 mmol, 2.2 eq) and triethylamine (178 mg, 245 µL, 1.76 mmol, 3.7 eq) were added sequentially to the reaction mixture again , and continued stirring overnight at 130°C. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (about 40 mL) and saturated NaHCO ₃ solution (about 10 mL). The aqueous layer was back extracted with ethyl acetate (about 40 mL). The organic layer was washed with water (about 5 mL) and brine (about 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, DCM/MeOH 0% to 20% MeOH) to afford the title compound (56 mg, 44% yield) as a yellow solid. LCMS m/z: 250.0 [M+H] ⁺ , ESI pos.

step B : 5- chlorine -2-[2-(1 H - imidazole -5- methylamino ) zozolo [4,5- b ] pyridine -5- base ]-3- methyl - Phenol; Formic acid

Following GP2a , (5-chloroazolo[4,5- b ]pyridin-2-yl)-( 1H -imidazol-5-ylmethyl)amine (20 mg, 78.5 µmol, 1.0 eq) was mixed with ( 4-Chloro-2-hydroxy-6-methyl-phenyl)boronic acid (CAS # 1207961-50-9, 28.7 mg, 153.9 µmol, 1.96 eq) was reacted to give the title compound (7 mg, 18% ). LCMS m/z: 354.2 [MH] ^- , ESI neg. Example 68 : ( 3R , 5R )-5-[[5-(4- chloro -2- hydroxyl -6- methyl - phenyl ) oxazolo [4,5- b ] pyridin -2- yl ] Amino ]-1- ethyl - piperidin -3- ol; formic acid

step A : (3 R ,5 R )-3-[(5- Chlorazolo [4,5- b ] pyridine -2- base ) Amino ]-5- hydroxyl - piperidine -1- Tertiary butyl formate

Following GP1 , 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (361 mg, 1.71 mmol, 1.0 eq) was mixed with (3 R ,5 R )-3-amino- 5-Hydroxy-piperidine-1-carboxylic acid tert- butyl ester (443.6 mg, 2.05 mmol, 1.2 eq) was reacted to give the title compound (690 mg, 99% yield) as a pale yellow solid. This compound was used in the next step without further purification. LCMS m/z: 369.2; 371.2 [M+H] ⁺ , ESI pos.

step B : (3 R ,5 R )-5-[(5- Chlorazolo [4,5- b ] pyridine -2- base ) Amino ] piperidine -3- alcohol; hydrochloride

To (3 R ,5 R )-3-[(5-chloroazolo[4,5- b ]pyridin-2-yl)amino]-5-hydroxy-piperidine-1-carboxylic acid tris at room temperature To a solution of butyl ester (690 mg, 1.68 mmol, 1.0 eq) in DCM (16 mL) and MeOH (8 mL) was added dropwise 4 M HCl in 1,4-dioxane (4.2 mL, 16.8 mmol , 10 eq). The reaction mixture was stirred at 23°C for 16 hours. The reaction mixture was concentrated in vacuo to give the crude title compound (632 mg, 98% yield) as a light brown foam, which was used in the next step without further purification. LCMS: m/z 269.1; 271.1 [M+H] ⁺ , ESI pos.

step C : (3 R ,5 R )-5-[(5- Chlorazolo [4,5- b ] pyridine -2- base ) Amino ]-1- Ethyl - piperidine -3- alcohol

According to GP4 , ( 3R , 5R )-5-[(5-chloroazolo[4,5- b ]pyridin-2-yl)amino]piperidin-3-ol; hydrochloride (632 mg, 1.66 mmol, 1.0 eq) was reacted with acetaldehyde (182.5 mg, 234 µL, 4.14 mmol, 2.5 eq) to give the title compound (255 mg, 49%) as a light brown foam. LCMS m/z: 297.2; 299.2 [M+H] ⁺ , ESI pos.

step D. : (3 R ,5 R )-5-[[5-(4- chlorine -2- hydroxyl -6- methyl - Phenyl ) zozolo [4,5- b ] pyridine -2- base ] Amino ]-1- Ethyl - piperidine -3- alcohol; formic acid

According to GP2a , ( 3R , 5R )-5-[(5-chloroazolo[4,5- b ]pyridin-2-yl)amino]-1-ethyl-piperidin-3-ol (106 mg, 357 µmol, 1.0 eq) was reacted with (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (CAS # 1207961-50-9, 133 mg, 714 µmol, 2.0 eq) to The title compound was obtained as a white amorphous lyophilized solid (18 mg, 11% yield). LCMS m/z: 401.2; 403.2 [MH] ^- , ESI neg. Example 69 : 3,6- Dimethyl -2-[2-[[(3 R )-1- methyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridine -5 -yl ] phenol _

step A : [5-(2- Methoxy -3,6- Dimethyl - Phenyl ) zozolo [4,5-b] pyridine -2- base ]-[(3 R )-1- methyl -3- piperidinyl ] amine

Under stirring, 5-chloro-N-[(3 R )-1-methyl-3-piperidinyl]oxazolo in 1,4-dioxane (2 mL) and water (1 mL) [4,5-b]pyridin-2-amine ( Example 15 , step 1) (41 mg, 153.7 µmol, 1.0 eq) and 2-(2-methoxy-3,6-dimethyl-phenyl) Potassium carbonate (95.6 mg, 691.7 µmol, 4.5 eq). Then, the yellow reaction solution was flushed with argon for 3 minutes, and then 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(ii) DCM complex (18.8 mg, 23.06 µmol, 0.15 eq). The dark reddish brown reaction mixture was sealed and stirred at 95°C for 3 hours. The dark brown/black reaction mixture was cooled to room temperature and 2-(2-methoxy-3,6-dimethyl-phenyl)-4,4,5,5-tetramethyl -1,3,2-Dioxaborolane (80.6 mg, 307.4 µmol, 2.0 eq) and cesium carbonate (100.2 mg, 307.4 µmol, 2.0 eq). Then, the dark brown/black reaction suspension was flushed with argon for 3 minutes before adding XPhos Pd G3 (19.5 mg, 23.1 μmol, 0.15 eq) with stirring at room temperature. The dark brown/black reaction mixture was flushed again with argon for 3 minutes, sealed and stirred at 100°C for 16 hours. After cooling to room temperature, the mixture was extracted twice with DCM (2 x 50 mL) and with saturated NH ₄ Cl solution (20 mL). The organic layer was washed with water (20 mL) and brine (20 mL). The aqueous layer was back extracted with DCM (40 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered off and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 0% to 10% methanol in DCM) to afford the title compound (26 mg, 46%) as a purple foam. LCMS m/z: 365.3 [MH] ^- , ESI neg.

step B : 3,6- Dimethyl -2-[2-[[(3 R )-1- methyl -3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ] phenol

Under stirring, to [5-(2-methoxy-3,6-dimethyl-phenyl)oxazolo[4,5- b ]pyridin-2-yl]-[(3 R )-1 To a suspension of -methyl-3-piperidinyl]amine (26 mg, 70 µmol, 1.0 eq) in DCM (1 mL) was added a solution of 1 M boron tribromide in DCM at 0°C (936 mg , 360 µL, 360 µmol, 5.1 eq), a brown suspension was obtained. The brown reaction mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. With vigorous stirring, the light brown reaction suspension was cooled with ice, then saturated aqueous NaHCO ₃ (10 mL) was slowly added dropwise. Then, the reaction mixture was transferred in 5 mL DCM to a separatory funnel and extracted twice with DCM (2 x 30 mL). The organic phase was washed with water (10 mL) and brine (10 mL). The aqueous phase was back extracted with DCM (20 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered off and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Gemini NX, 12 nm, 5 µm, 100 x 30 mm; gradient: MeCN/water+0.1% TEA) to give the title compound (10 mg, yield rate 40%). LCMS m/z: 351.3 [MH] ^- , ESI neg. Example 70 : ( 3R , 5R )-5-[[5-(4- chloro -2- hydroxyl -6- methyl - phenyl ) oxazolo [4,5- b ] pyridin -2- yl ] Amino ]-1- ethyl - piperidin -3- ol; formic acid

The title compound was obtained as a white amorphous lyophilized solid from ( 3S , 5R )-5-[(5-chlorooxazolo[4,5- b ] pyridin-2-yl)amino]-1-ethyl-piperidin-3-ol ( Example 28 , step 3 ) and 3,5-dimethyl-2-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)phenol ( Example 123 , Step D ) The preparation was initiated. LCMS: m/z 381.4 [MH] ^- , ESI neg. Examples 72a and 72b : 4-[2-[(3a S ,7a R )-6- ethyl -3,3a,4,5,7,7a- hexahydro - 2H - pyrrolo [2,3- c ] pyridin -1- yl ] oxazolo [4,5- b ] pyridin -5- yl ]-3- hydroxy -5 - methyl - benzonitrile or 4-[2-[(3a R ,7a S )- 6- Ethyl -3,3a,4,5,7,7a- hexahydro -2 H - pyrrolo [2,3- c ] pyridin -1- yl ] oxazolo [ 4,5- b ] pyridine- 5- yl ]-3- hydroxy -5- methyl - benzonitrile and 4-[2-[(3a R ,7a S )-6- ethyl -3,3a,4,5,7,7a- hexahydro -2 H - pyrrolo [2,3- c ] pyridin -1- yl ] oxazolo [4,5- b ] pyridin -5- yl ]-3- hydroxy -5- methyl - benzonitrile or 4- [2-[(3a S ,7a R )-6- ethyl -3,3a,4,5,7,7a- hexahydro - 2H - pyrrolo [2,3- c ] pyridin -1- yl ] Zazolo [4,5- b ] pyridin -5- yl ]-3- hydroxy -5- methyl - benzonitrile

step 1 : 1-(5- Chlorazolo [4,5- b ] pyridine -2- base )-3,3a,4,5,7,7a- Hexahydro -2H- pyrrolo [2,3- c ] pyridine -6- Tertiary butyl formate

To 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 250 mg, 1.18 mmol, 1.00 eq) in 1,4-dioxane ( 2.5 mL) was sequentially added tertiary butyl 1,2,3,3a,4,5,7,7a-octahydropyrrolo[2,3- c ]pyridine-6- carboxylate (CAS # 1196147- 27-9, 308 mg, 1.36 mmol, 1.15 eq) and triethylamine (138 mg, 0.190 mL, 1.36 mmol, 1.15 eq). The reaction mixture was stirred at 105°C for 16 hours and at 115°C for 2 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated NaHCO ₃ solution. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE-HM and purified by flash chromatography (silica gel, 25 g, gradient: 0% to 70% ethyl acetate in heptane) to give the title compound (366 mg, yield 78%). LCMS: m/z 379.2 [M+H] ⁺ , ESI pos.

step 2 : 2-(2,3,3a,4,5,6,7,7a- Octahydropyrrolo [2,3- c ] pyridine -1- base )-5- chlorine - zozolo [4,5- b ] Pyridine hydrochloride

The title compound was obtained as an off-white solid, LCMS: m/z 279.2 [M+H] ⁺ , ESI pos, from 1-(5-chlorooxazolo[ 4,5- b ]pyridin-2-yl)-3,3a,4,5,7,7a-hexahydro- 2H -pyrrolo[2,3- c ]pyridine-6-carboxylic acid tertiary butyl ester ( Step 1 ) Start preparation.

step 3 : 5- chlorine -2-(6- Ethyl -3,3a,4,5,7,7a- Hexahydro -2H- pyrrolo [2,3- c ] pyridine -1- base ) zozolo [4,5- b ] pyridine

Under ice cooling, to the above 2-(2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3- c ]pyridin-1-yl)-5-chloro-㗁Azolo[4,5- b ]pyridine hydrochloride ( step 2 ) (325 mg, 0.88 mmol, 1.00 eq, 85% purity) To a suspension in DCM (5.5 mL) was added acetaldehyde (CAS # 75 -07-0, 94 mg, 0.120 mL, 2.12 mmol, 2.42 eq) and sodium acetate (145 mg, 1.77 mmol, 2.02 eq). Sodium triacetyloxyborohydride (280 mg, 1.32 mmol, 1.51 eq) was added in three portions at 0 °C. After the addition was complete, the ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was carefully quenched with saturated aqueous NaHCO ₃ and extracted three times with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 25 g, gradient: 0% to 10% methanol in DCM) to give the title compound as an orange solid (183 mg, yielding rate of 65%). LCMS: m/z 307.2 [M+H] ⁺ , ESI pos.

step 4 : 4-[2-(6- Ethyl -3,3a,4,5,7,7a- Hexahydro -2H- pyrrolo [2,3- c ] pyridine -1- base ) zozolo [4,5-b] pyridine -5- base ]-3- hydroxyl -5- methyl - Benzonitrile

The title compound was obtained as an orange foam from 5 -chloro-2-(6-ethyl-3,3a,4,5,7,7a- Hexahydro- 2H -pyrrolo[2,3- c ]pyridin-1-yl)oxazolo[4,5- b ]pyridine ( step 3 ) and (4-cyano-2-hydroxy-6-methyl yl-phenyl)boronic acid ( Example 25 , Step D ) was prepared starting. LCMS: m/z 404.3 [M+H] ⁺ , ESI pos.

step 5 : 4-[2-[(3a S ,7a R )-6- Ethyl -3,3a,4,5,7,7a- Hexahydro -2H- pyrrolo [2,3- c ] pyridine -1- base ] zozolo [4,5- b ] pyridine -5- base ]-3- hydroxyl -5- methyl - Benzonitrile and 4-[2-[(3a R , 7aS )-6- Ethyl -3,3a,4,5,7,7a- Hexahydro -2H- pyrrolo [2,3- c ] pyridine -1- base ] zozolo [4,5- b ] pyridine -5- base ]-3- hydroxyl -5- methyl - Benzonitrile

4-[2-(6-Ethyl-3,3a,4,5,7,7a-hexahydro-2 H -pyrrolo[2,3- c ]pyridin-1-yl)oxazolo[4, 5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile ( Example 72 , step 4 ) (154 mg, 0.34 mmol, 1.00 eq) was chirally separated by SFC (column: Chiralpak AD, eluent B: 25% methanol + 0.2% diethylamine) to obtain two enantiomers: light brown foam Example 72a (eluted first, retention time = 2.5 minutes) (58 mg, Yield 40%), LCMS: m/z 404.3 [M+H] ⁺ , ESI pos; and Example 72b (second elution, retention time = 2.9 minutes), which was separated by SFC (column: Chiralpak AD , eluent B: 25% methanol+0.2% diethylamine) was purified again to obtain Example 72b as light brown foam (second eluting, retention time=2.9 minutes) (46 mg, yield 32%); LCMS: m/z 404.3 [M+H] ⁺ , ESI pos. Example 73 : 5-[5-(4- chloro -2- hydroxyl -6 - methyl - phenyl ) oxazolo [4,5-b] pyridin -2- yl ] piperidin -2- one

step A : 5-(5- bromozolo [4,5-b] pyridine -2- base ) piperidine -2- ketone

Add 6-oxopiperidine-3-carboxylic acid (41.0 mg, 0.29 mmol, 1.08 eq) and 2-amino-6-bromopyridin-3-ol (50.0 mg, 0.26 mmol, 1.0 eq) to polyphosphoric acid (1.0 mL), and the viscous mixture was heated and stirred at 100°C for 48 hours. The reaction mixture was spooned out and added to a separatory funnel containing saturated aqueous NaHCO3 (30 mL), causing vigorous bubbling, when bubbling had ceased, DCM (30 mL) was added and shaken. The separated aqueous layer was further extracted with DCM (2 x 30 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give the title compound (38.0 mg, 43% yield) as a light brown solid. LCMS m/z 295.7 ( ³⁵ Cl) [M+H]+, ESI pos.

step B : 5-[5-(4- chlorine -2- hydroxyl -6- methyl - Phenyl ) zozolo [4,5-b] pyridine -2- base ] piperidine -2- ketone

5-(5-Bromozozolo[4,5-b]pyridin-2-yl)piperidin-2-one (38.0 mg, 0.13 mmol, 1.0 eq), (4-chloro-2-hydroxyl-6 -Methyl-phenyl)boronic acid (CAS # 1207961-50-9, 26.0 mg, 0.14 mmol, 1.09 eq) and potassium carbonate (45.0 mg, 0.33 mmol, 2.54 eq) in water (0.5 mL) and 1,4- The solution in dioxane (2 mL) was bubbled (with N ₂ while being sonicated) for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (5.0 mg, 0.01 mmol, 0.05 eq) was added and the reaction mixture was heated to 90°C for 80 minutes. The crude mixture was concentrated under reduced pressure and loaded onto silica. The crude product was purified by silica gel flash chromatography (24 g, 0% to 12% MeOH (containing 0.7M NH ₃ )/EtOAc) to afford the title compound (23.0 mg, 48% yield) as a light brown solid. LCMS m/z 358.1 ( ³⁵ Cl) [M+H]+, ESI pos. Examples 73a and 73b : ( 5S )-5-[5-(4- chloro -2- hydroxy -6 - methyl - phenyl ) oxazolo [4,5-b] pyridin -2- yl ] piperidine -2- one or (5 R )-5-[5-(4- chloro -2- hydroxy -6 - methyl - phenyl ) oxazolo [4,5-b] pyridin -2- yl ] piperidine -2- one and (5 R )-5-[5-(4- chloro -2- hydroxy -6 - methyl - phenyl ) oxazolo [4,5-b] pyridin -2- yl ] piperidine -2- one or (5 S )-5-[5-(4- chloro -2- hydroxy -6 - methyl - phenyl ) oxazolo [4,5-b] pyridin -2- yl ] piperidine -2- one

The above-mentioned 5-[5-(4-chloro-2-hydroxyl-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one (in Waters prep Chiral SFC on 15 with DAD for UV detection from 210 to 400 nm, 40 °C, 120 bar; column: Chiralpak IH 10 × 250 mm, 5 µm; flow rate 15 mL/min, 40% MeOH (0.1% ammonia), 60% CO ₂ ) The title compound was obtained after chiral separation to give 73a (7.1 mg, 15% yield) as an off-white solid (ee 95.2%) and 73b (5.9 mg, 13% yield) as an off-white solid ( ee: 92.6%). LCMS m/z 358.1; 360.1 (Cl isotope) [M+H] ⁺ , ESI pos. Example 74 : 5- Chloro -2-[2-[[(3 R )-1-(3,3- difluoropropyl )-3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridin -5- yl ]-3- methyl - phenol

step 1 : 4- Toluenesulfonic acid 3,3- difluoropropyl ester

To a solution of 3,3-difluoropropan-1-ol (CAS # 461-52-9, 500 mg, 0.452 mL, 5.20 mmol, 1.00 eq) in DCM (15.5 mL) under nitrogen was sequentially added triethyl Amine (1.32 g, 1.8 mL, 13.0 mmol, 2.50 eq) and 4-toluenesulfonyl chloride (CAS # 98-59-9, 1.19 g, 6.24 mmol, 1.20 eq). The reaction was stirred at room temperature for 3 hours. The reaction mixture was poured into NaHCO ₃ solution and extracted three times with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was taken up on silica gel and purified by flash chromatography (silica gel, 20 g, gradient: 0% to 30% ethyl acetate in heptane) to give the title compound (670 mg, yield rate 49%). LCMS not judged, not ionized.

step 2 : (3 R )-3-[[5-(4- chlorine -2- hydroxyl -6- methyl - Phenyl ) zozolo [4,5- b ] pyridine -2- base ] Amino ] piperidine -1- Tertiary butyl formate

The title compound was obtained as a pale yellow foam, LCMS: m/z 459.3 [M+H] ⁺ , ESI pos, from ( 3R )-3-[(5-chloro Ozozolo[4,5- b ]pyridin-2-yl)amino]piperidine-1-carboxylic acid tertiary butyl ester ( Example 61 , step A ) and (4-chloro-2-hydroxyl-6-methyl -Phenyl)boronic acid ( CAS# 1207961-50-9 ) was prepared initially.

step 3 : 5- chlorine -3- methyl -2-[2-[[(3 R )-3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ] phenol

To (3 R )-3-[[5-(4-chloro-2-hydroxyl-6-methyl-phenyl)oxazolo[4,5- b ]pyridin-2-yl]amino]piperidine - To a solution of tert-butyl 1-carboxylate ( Example 74 , step 2 ) (58 mg, 0.12 mmol, 1.00 eq) in DCM (0.32 mL) and methanol (0.16 mL) was added 4 M HCl in dioxane solution (0.30 mL, 1.20 mmol, 10.0 eq). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM/methanol (9:1), basified with saturated aqueous NaHCO ₃ and extracted three times with a mixture of DCM/methanol (9:1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and flash-chromatographed (Si-amine, gradient: 0% to 10% methanol in ethyl acetate) to afford the title compound (25 mg, yield rate 55%). LCMS: m/z 359.2 [M+H] ⁺ , ESI pos.

step 4 : 5- chlorine -2-[2-[[(3 R )-1-(3,3- Difluoropropyl )-3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl - phenol

To 5-chloro-3-methyl-2-[2-[[(3 R )-3-piperidinyl]amino]oxazolo[4,5- b ]pyridin-5-yl]phenol ( example 74 , Step 3 ) (20 mg, 0.05 mmol, 1.00 eq, 90% purity) To a mixture in THF (0.16 mL) and N , N -dimethylformamide (0.16 mL) was added N , N -di Isopropylethylamine (19 mg, 0.025 mL, 0.14 mmol, 2.85 eq) followed by dropwise addition of 3,3-difluoropropyl 4-methylbenzenesulfonate ( Example 74 , step 1 ) (16 mg, 0.06 mmol, 1.21 eq). The reaction mixture was stirred at 50°C for 16 hours, then 3,3-difluoropropyl 4-methylbenzenesulfonate (8 mg, 0.03 mmol, 0.61 eq) and N , N -dimethylformyl were added at room temperature amine (0.16 mL), and the reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was cooled to room temperature, then extracted with ethyl acetate and saturated 10% LiCl solution. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed twice with 10% aqueous LiCl, once with water, and once with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 4 g, gradient: 0% to 100% ethyl acetate in heptane) to afford the title compound (14 mg, yield 61%). LCMS: m/z 437.2 [M+H] ⁺ , ESI pos. Example 75 : 5- Chloro -3- methyl -2-[2-[[(3 R )-1-[(3- hydroxycyclobutyl ) methyl ]-3- piperidinyl ] amino ] oxazole And- [4,5-b] pyridin -5- yl ] phenol

step A : (3 R )-3-[(5- bromozolo [4,5-b] pyridine -2- base ) Amino ] piperidine -1- Tertiary butyl formate

( R )-1-Boc-3-aminopiperidine (1.05 g, 5.24 mmol, 1.29 eq) and triethylamine (1.71 mL, 12.24 mmol, 3.0 eq) were added to 5-bromo-2-methylhydrogen Thio-oxazolo[4,5-b]pyridine (1.0 g, 4.08 mmol, 1.0 eq) was stirred in 1,4-dioxane (20 mL) and the reaction mixture was heated to 90 °C Lasts 16 hours. Additional ( R )-1-Boc-3-aminopiperidine (1.05 g, 5.24 mmol, 1.29 eq) and triethylamine (1.71 mL, 12.24 mmol, 3.0 eq) were then added to the reaction mixture, which was Heat to 90°C for a further 18 hours. The reaction mixture was cooled to room temperature, diluted with NaHCO ₃ (10 mL) and EtOAc (10 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 10 mL), and the combined organic phases were concentrated in vacuo. The crude product was purified by column chromatography (silica gel, cartridge, 0% to 100% (EtOAc/isohexane)) to afford the title compound (1.6 g, 86% yield) as a light brown foam. LCMS m/z 397.2; 399.3 (Br isotope) [M+H] ⁺ , ESI pos.

step B : 5- bromine - N -[(3 R )-3- piperidinyl ] zozolo [4,5-b] pyridine -2- Amine; dihydrochloride

(3 R )-3-[(5-bromozozolo[4,5-b]pyridin-2-yl)amino]piperidine-1-carboxylic acid tertiary butyl ester ( example 75 , step To a stirred solution of A ) (2.0 g, 5.03 mmol, 1.0 eq) in 1,4-dioxane (12 mL) was added 4M HCl in dioxane (5.0 mL, 20.0 mmol, 3.97 eq), and The reaction was warmed to room temperature and stirred for 30 minutes. MeOH (5 mL) was then added, and the reaction was stirred for an additional 1.5 h at room temperature. The reaction was concentrated under reduced pressure to afford the title compound (1.88 g, 89% yield) as an orange solid. LCMS m/z 297.1; 299.1 (Br isotope) [M+H] ⁺ , ESI pos.

step C : 3-[(3 R )-3-[(5- bromozolo [4,5-b] pyridine -2- base ) Amino ] piperidine -1- Carbonyl ]- Cyclobutanone

To 5-bromo- N -[( 3R )-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine; dihydrochloride ( Example 75 , Step B ) (245.0 mg, 0.58 mmol, 1.0 eq) to a stirred solution in DCM (5 mL) and N,N -diisopropylethylamine (500 µL, 2.87 mmol, 4.93 eq) was added 3-oxetanecarboxylic acid (73.0 mg , 0.64 mmol, 1.1 eq) and O -(7-azabenzotriazol-1-yl) -N,N,N',N' -tetramethyluronium hexafluorophosphate (339.0 mg, 0.89 mmol, 1.53 eq), and the reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and loaded onto silica. The crude product was purified by silica chromatography (40 g, 0% to 10% MeOH (0.7 M NH3):EtOAc) to afford the title compound (373.0 mg, 98% yield) as a light brown oil. LCMS m/z 393.2; 395.2 (Br isotope) [M+H] ⁺ , ESI pos.

step D. : 3-[(3 R )-3-[[5-(4- chlorine -2- hydroxyl -6- methyl - Phenyl ) zozolo [4,5-b] pyridine -2- base ] Amino ] piperidine -1- Carbonyl ] Cyclobutanone

3-[(3 R )-3-[(5-Bromozozolo[4,5-b]pyridin-2-yl)amino]piperidine-1-carbonyl]cyclobutanone (295 mg, 0.56 mmol, 1.0 eq), (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (CAS # 1207961-50-9, 115 mg, 0.62 mmol, 1.1 eq) and potassium carbonate (196.0 mg, 1.42 mmol, 2.52 eq) in 1,4-dioxane (5 mL) and water (1 mL) was bubbled (with N ₂ sparged while sonicating) for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (22.0 mg, 0.03 mmol, 0.05 eq) was added and the reaction mixture was heated to 90°C for 2 hours. The crude mixture was concentrated under reduced pressure and loaded onto silica. The crude reaction mixture was purified by column chromatography (silica gel, 0% to 10% MeOH (0.7 M NH ₃ ):EtOAc) to afford the title compound (182 mg, 68% yield) as a white solid. LCMS m/z 455.3; 457.2 (Br isotope) [M+H] ⁺ , ESI pos.

step E. : 5- chlorine -3- methyl -2-[2-[[(3 R )-1-[(3- Hydroxycyclobutyl ) methyl ]-3- piperidinyl ] Amino ]- zozolo -[4,5-b] pyridine -5- base ] phenol

3-[(3 R )-3-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl at 0°C ]amino]piperidine-1-carbonyl]cyclobutanone (141 mg, 0.31 mmol, 1.0 eq) in THF (9 mL) was added dropwise to a stirred solution of lithium aluminum hydride (2.4 M in THF) (425 µL , 1.02 mmol, 3.29 eq). The reaction was stirred for 30 minutes, then allowed to warm to room temperature and stirred for 3.5 hours. The reaction mixture was quenched with MeOH (3 mL) and stirred overnight. The crude mixture was concentrated under reduced pressure and loaded onto silica. The crude reaction mixture was purified by column chromatography (silica gel, 0% to 20% MeOH (0.7M NH ₃ ):DCM), followed by reverse phase preparative HPLC (Waters 2767 sample manager, Waters 2545 binary gradient Module, Waters System Fluidics Organizer, Waters 515 ACD Pump, Waters 515 Makeup Pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters X-Select CSH C18 ODB Preparative Column (130Å, 5 µm , 30 mm × 100 mm) (flow rate of 40 mL·min-1, eluting with a gradient of 0.1% formic acid in water-MeCN within 12.5 minutes, using PDA and QDA and ELS detectors to obtain all wavelength at UV). Throughout the method, the on-column dilution pump delivered 2 mL min-1 of methanol, which is included in the MeCN percentages below. Gradient profile: 0.0 to 0.5 minutes, 5% MeCN; 0.5 minutes to 10.5 minutes, increments from 5% MeCN to 32.5% MeCN; 10.5 minutes to 10.6 minutes, increments from 32.5% MeCN to 100% MeCN; 10.6 minutes to 12.5 minutes, Keep at 100% MeCN. The clean fractions were evaporated in Genevac to give the title compound (43.6 mg, 31% yield) as a white solid. LCMS m/z 433.3; 435.3 (Br isotope) [M+H] ⁺ , ESI pos. Example 76 : 5- Chloro -2-[2-( 1H - imidazol - 2-ylmethylamino ) oxazolo [4,5- b ] pyridin -5- yl ]-3- methyl - phenol

step 1 : 5- chlorine -N-(1 H- imidazole -2- methyl group ) zozolo [4,5- b ] pyridine -2- amine

To 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS # 1783370-92-2, 150 mg, 0.71 mmol, 1.00 eq) in 1,4-dioxane ( 1.5 mL) was added sequentially with 1 H -imidazol-2-ylmethylamine dihydrochloride (CAS # 53332-80-2, 146 mg, 0.86 mmol, 1.21 eq) and triethylamine (290 mg, 0.400 mL, 2.87 mmol, 4.04 eq). The brown suspension was stirred at 90°C for 16 hours. N -Methyl-2-pyrrolidone (1.0 mL) was added at room temperature, and the reaction mixture was stirred at 140°C for 3.5 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and 5% aqueous LiCl. The aqueous layer was back extracted with ethyl acetate. The organic layer was washed three times with 5% aqueous LiCl, once with water and once with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 100% in DCM (DCM:methanol: _NH4OH 9:1:0.05)) , to afford the title compound (132 mg, 67% yield, 90% purity) as a pale yellow solid. LCMS: m/z 250.0 [M+H] ⁺ , ESI pos.

step 2 : 5- chlorine -2-[2-(1 H - imidazole -2- methylamino ) zozolo [4,5- b ] pyridine -5- base ]-3- methyl - phenol

The title compound was obtained as a light brown solid, LCMS: m/z 356.1 [M+H] ⁺ , ESI pos, from 5-chloro-N-( 1H -imidazole- 2-ylmethyl)oxazolo[4,5- b ]pyridin-2-amine ( Example 76 , Step 1 ) and (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid ( CAS# 1207961-50-9 ) to begin preparation. Example 77 : 2-[2-[3-( Hydroxymethyl )-1- piperidinyl ] oxazolo [4,5- b ] pyridin -5- yl ]-3- methyl -5-( trifluoro methyl ) phenol

step 1 : [1-(5- Chlorazolo [4,5- b ] pyridine -2- base )-3- piperidinyl ] Methanol

5-Chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS # 1783370-92-2, 60 mg, 0.28 mmol, 1.00 eq), 3-piperidinylmethanol (CAS # 4606-65-9, 36 mg, 0.31 mmol, 1.10 eq) and triethylamine (33 mg, 0.045 mL, 0.32 mmol, 1.14 eq) in 1,4-dioxane (0.60 mL) in 90 °C and stirred for 16 hours. The reaction mixture was then extracted with ethyl acetate and saturated aqueous NaHCO ₃ . The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 10% methanol in DCM) to give the title compound as a yellow oil (80 mg, quantitative yield Rate). LCMS: m/z 268.1 [M+H] ⁺ , ESI pos.

step 2 : 2-[2-[3-( Hydroxymethyl )-1- piperidinyl ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

The title compound was obtained as an off-white foam, LCMS: m/z 408.3 [M+H] ⁺ , ESI pos, from [1-(5-chlorooxazolo[ 4,5- b ]pyridin-2-yl)-3-piperidinyl]methanol ( Example 77 , step 1 ) and 3-methyl-2-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS # 2557358-38-8) was prepared initially. Example 78 : 2-[2-[4-( Hydroxymethyl )-1- piperidinyl ] oxazolo [4,5- b ] pyridin -5- yl ]-3- methyl -5-( trifluoro methyl ) phenol

step 1 : [1-(5- Chlorazolo [4,5- b ] pyridine -2- base )-4- piperidinyl ] Methanol

5-Chloro-2-(methylthio)oxazolo[4,5-b]pyridine (CAS # 1783370-92-2, 50 mg, 0.24 mmol, 1.00 eq), 4-piperidinylmethanol (CAS # 6457-49-4, 30 mg, 0.26 mmol, 1.10 eq) and triethylamine (28 mg, 0.038 mL, 0.27 mmol, 1.15 eq) in 1,4-dioxane (0.50 mL) in 90 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, then extracted with ethyl acetate and saturated aqueous NaHCO ₃ . The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM and purified by flash chromatography (silica gel, 12 g, gradient: 0% to 10% methanol in DCM) to give the title compound as an off-white solid (65 mg, yield 97 %). LCMS: m/z 268.3 [M+H] ⁺ , ESI pos.

step 2 : [1-[5-[2- Methoxy -6- methyl -4-( Trifluoromethyl ) Phenyl ] zozolo [4,5- b ] pyridine -2- base ]-4- piperidinyl ] Methanol

The title compound was obtained as a pale yellow waxy solid from [1-(5-chlorooxazolo[4,5- b ]pyridin-2-yl)-4- using chemistry similar to that described in Example 19 . Piperidinyl]methanol ( Example 78 , step 1 ) and 2-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl -1,3,2-Dioxaborolane (CAS # 2557358-25-3) was prepared initially. LCMS: m/z 422.3 [M+H] ⁺ , ESI pos.

step 3 : 2-[2-[4-( Hydroxymethyl )-1- piperidinyl ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

The title compound was obtained as a white solid from [1-[5-[2-methoxy-6-methyl-4-(trifluoromethyl) using chemistry similar to that described in Example 3 (Step 3). )phenyl]oxazolo[4,5- b ]pyridin-2-yl]-4-piperidinyl]methanol ( Example 78 , step 2 ) and boron tribromide (1 M solution in dichloromethane ) to start preparation. LCMS: m/z 408.3 [M+H] ⁺ , ESI pos. Example 79 : 2-[2-(1- Ethyl -1,7 -diazaspiro [3.5] non -7- yl ) oxazolo [4,5- b ] pyridin - 5- yl ]-3- Methyl -5-( trifluoromethyl ) phenol

step 1 : 5- chlorine -2-(1- Ethyl -1,7- Diazaspiro [3.5] the ninth of the ten Heavenly Stems -7- base ) zozolo [4,5- b ] pyridine

To 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370-92-2, 80 mg, 0.38 mmol, 1.00 eq) in 1,4-dioxane ( 0.80 mL) was added sequentially with 1-ethyl-1,7-diazaspiro[3.5]nonane (CAS # 1422139-09-0, 66 mg, 0.43 mmol, 1.13 eq) and triethylamine ( 44 mg, 0.060 mL, 0.43 mmol, 1.14 eq). The brown solution was stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated aqueous NaHCO ₃ . The aqueous layer was back extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was taken up on ISOLUTE HM-N and purified by flash chromatography (silica gel, gradient: 0% to 100% in DCM (DCM:methanol: _NH4OH 9:1:0.05)) to give The title compound (106 mg, 87% yield) as a pale yellow solid. LCMS: m/z 307.2 [M+H] ⁺ , ESI pos.

step 2 : 2-[2-(1- Ethyl -1,7- Diazaspiro [3.5] the ninth of the ten Heavenly Stems -7- base ) zozolo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

The title compound was obtained as an off-white foam, LCMS: m/z 447.3 [M+H] ⁺ , ESI pos, from 5-chloro-2-(1-ethyl -1,7-diazaspiro[3.5]non-7-yl)oxazolo[4,5- b ]pyridine ( Example 79 , step 1 ) and 3-methyl-2-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (CAS # 2557358-38-8) was prepared initially. Example 80 : 3- Hydroxy -5- methyl -4-[2-[ rel- (4aS,7aR)-6- ethyl -2,3,4a,5,7,7a- hexahydropyrrolo [3, 4-b][1,4] oxazin -4- yl ] oxazolo [4,5-b] pyridin -5- yl ] benzonitrile

step A : rel -(4aS,7aR)-6- Ethyl -2,3,4a,5,7,7a- Hexahydropyrrolo [3,4-b][1,4] oxazine -4- Tertiary butyl formate

In a sealed tube, to commercially available rel- (4aS,7aR)-3,4a,5,6,7,7a-hexahydro- 2H -pyrrolo[3,4-b][1,4 ] tert- butyl oxazine-4-carboxylate (CAS #1312131-49-9, 150 mg, 657 µmol, 1.0 eq) To a mixture in THF (3.1 mL) was added N,N -diisopropylethylamine (212 mg, 287 µL, 1.6 mmol, 2.5 eq), then ethyl iodide (123 mg, 63.7 µL, 788 µmol, 1.2 eq) was added dropwise at room temperature. Then, the mixture was stirred at 40 °C for 6 h 30 min and then at room temperature overnight. The reaction mixture was extracted with ethyl acetate, sodium bicarbonate and water. The aqueous layer was back extracted twice with ethyl acetate. The combined organic layers were washed with brine and water, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude title compound (149 mg, 84% yield) was obtained as a yellow viscous oil, which was used in the next step without purification. LCMS m/z: 257.2 [M+H] ⁺ , ESI pos.

step B : rel -(4aS,7aR)-6- Ethyl -3,4,4a,5,7,7a- Hexahydro -2H- pyrrolo [3,4-b][1,4] oxazine; hydrochloride

To rel -(4aS,7aR)-6-ethyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylic acid tertiary Butyl ester (147 mg, 544 µmol, 1.0 eq) in dichloromethane (4.2 mL) and methanol (2.1 mL) was added dropwise with 4 M HCl in dioxane (1.77 g, 1.36 mL, 5.44 mmol , 10 eq). The reaction mixture was stirred overnight at room temperature under argon gas. The solvent was evaporated in vacuo. The title compound was obtained as a pale yellow solid (154 mg, 110% yield) which was used in the next step without purification. LCMS m/z: 157.1 [M+H] ⁺ , ESI pos.

step C : 5- chlorine -2-[ rel -(4aS,7aR)-6- Ethyl -2,3,4a,5,7,7a- Hexahydropyrrolo [3,4-b][1,4] oxazine -4- base ] zozolo [4,5-b] pyridine

According to GP1 , 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (120 mg, 586 µmol, 1.0 eq) was mixed with rel-(4aS,7aR)-6-ethyl- 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine; hydrochloride (150.6 mg, 703.31 µmol, 1.2 eq) at 120℃ React overnight. After addition of NMP (0.5 mL), stirring was continued at 150 °C for 14 hours. After work-up, the crude product was purified by flash chromatography (Gradient: 0% to 80% DCM:MeOH: _NH4OH (110:10:1) in DCM) to afford the title compound as a brown solid ( 69.5 mg, yield 37%). LCMS: 309.2 [M+H] ⁺ , ESI pos.

step D. : 3- hydroxyl -5- methyl -4-[2-[rel-(4aS,7aR)-6- Ethyl -2,3,4a,5,7,7a- Hexahydropyrrolo [3,4-b][1,4] oxazine -4- base ] zozolo [4,5-b] pyridine -5- base ] Benzonitrile

According to GP2b , 5-chloro-2-[ rel- (4aS,7aR)-6-ethyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1, 4] oxazin-4-yl] oxazolo[4,5-b]pyridine (68 mg, 220 µmol, 1.0 eq) with (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid ( Example 25 , Step D ) (66.3 mg, 374 µmol, 1.7 eq) Reaction. In HPLC chromatography (column: YMC-Triart C ₁₈ , 12 nm, 5 µm, 100 × 30 mm; gradient: 15-35-50-100 MeCN in water; 11 minutes; MeCN/(water+0.1% TEA )) After purification, the pure product was obtained as a white solid (20.7 mg, 22% yield). LCMS: 406.3 [M+H] ⁺ , ESI pos. Example 81 : 3- Hydroxy -5- methyl -4-[2-(7- methyl -2,3,4,4a,5,6,8,8a -octahydro -1,7- phenidine -1 -yl ) oxazolo [4,5-b] pyridin - 5 - yl ] benzonitrile

step A : 5- chlorine -2-(7- methyl -2,3,4,4a,5,6,8,8a- Octahydro -1,7- Hedidine -1- base ) zozolo [4,5-b] pyridine

According to GP1 , 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (225 mg, 1.1 mmol, 1.0 eq) was mixed with 7-methyl-2,3,4,4a, 5,6,8,8a-Octahydro-1 H -1,7-furidine; Dihydrochloride (300 mg, 1.32 mmol, 1.2 eq) Reacted in a sealed tube at 120°C for 2.5 hours. Then, NMP (3 mL) was added, and the reaction was stirred at 140 °C overnight. After work-up and purification by flash chromatography (Gradient: 0% to 10% MeOH in DCM), the title compound was obtained as a light brown viscous oil (36.8 mg, 10% yield). LCMS: 307.2 [M+H] ⁺ , ESI pos.

step B : 3- hydroxyl -5- methyl -4-[2-(7- methyl -2,3,4,4a,5,6,8,8a- Octahydro -1,7- Hedidine -1- base ) zozolo [4,5-b] pyridine -5- base ] Benzonitrile

According to GP2b , 5-chloro-2-(7-methyl-2,3,4,4a,5,6,8,8a-octahydro-1,7-oxidin-1-yl)oxazolo[ 4,5-b]pyridine (35 mg, 108 µmol, 1.0 eq) was reacted with (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid ( Example 25 , Step D ) to give a white solid The title compound (5.8 mg, 13% yield). LCMS: 402.3 [MH] ^- , ESI neg. Example 82 : 2- Hydroxy -4- methyl -3-[2-[[(3 R )-1- methyl -3- piperidinyl ] amino ] oxazolo [4,5-b ] pyridine- 5- yl ] benzonitrile; 2,2,2- trifluoroacetic acid

step A : 3- bromine -2- hydroxyl -4- Methylbenzonitrile

To a mixture of diisopropylamine (3.03 g, 30.0 mmol, 1.0 eq) and NBS (6.42 g, 36.05 mmol, 1.2 eq) in toluene (60 mL) was added 2-hydroxy-4-methyl at 0 °C Benzonitrile (4.0 g, 30.04 mmol, 1.0 eq), then stirred at 20°C for 12 hours. The above reaction solution was diluted with water (200 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1:0 to 2:1) to obtain the title compound (1.10 g, yield 17%) as a yellow solid. ¹ H NMR (CDCl _3, 400 MHz) δ [ppm]: 7.42 (d, 1H), 6.91 (d, 1H), 6.23 (br. s, 1H), 2.48 (s, 3H).

step B : 3- bromine -4- methyl -2-((2-( Trimethylsilyl ) Ethoxy ) Methoxy ) Benzonitrile

To a solution of 3-bromo-2-hydroxy-4-methylbenzonitrile (1.10 g, 5.19 mmol, 1.0 eq) in MeCN (10 mL) was added K ₂ CO ₃ (1.43 g, 10.4 mmol, 2.0 eq) , then added 2-(trimethylsilyl)ethoxymethyl chloride (1.38 mL, 7.78 mmol, 1.5 eq) and stirred at 20°C for 1 hour. The above reaction solution was diluted with water (50 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 10:1) to obtain the title compound (1.10 g, yield 62%) as yellow oil. ¹ H NMR (CDCl _3, 400 MHz) δ [ppm]: 7.44 (d, 1H), 7.10 (d, 1H), 5.34 (s, 2H), 4.09 - 3.96 (m, 2H), 2.49 (s, 3H) ), 1.08 - 1.01 (m, 2H), 0.05 (s, 9H).

step C : 4- methyl -3-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base )-2-((2-( Trimethylsilyl ) Ethoxy ) Methoxy ) Benzonitrile

Under nitrogen gas, 3-bromo-4-methyl-2-((2-(trimethylsilyl)ethoxy)methoxy)benzonitrile (1.0 g, 2.92 mmol, 1.0 eq ) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.09 g, 5.84 mmol, 2.0 eq) in THF (20 mL) To the solution in , iPrMgCl-LiCl (4.49 mL, 1.3 M solution in hexane, 2.0 eq) was added, followed by stirring at 20°C for 2 hours. The above reaction solution was quenched with sodium sulfite (150 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a yellow oil. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 10:1) to obtain the title compound (0.30 g, yield 26%) as yellow oil. ¹ H NMR (CDCl _3, 400 MHz) δ [ppm]: 7.50 (d, 1H), 6.95 (d, 1H), 5.24 (s, 2H), 4.03 - 3.88 (m, 2H), 2.45 (s, 3H) ), 1.40 (s, 12H), 1.08 - 0.97 (m, 2H), 0 (s, 9H).

step D. : ( R )-4- methyl -3-(2-((1- Methylpiperidine -3- base ) Amino ) zozolo [4,5-b] pyridine -5- base )-2-((2-( Trimethylsilyl ) Ethoxy ) Methoxy ) Benzonitrile

To 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-trimethylsilyl To a solution of ethoxymethoxy)benzonitrile (0.080 g, 0.21 mmol, 1.0 eq) in 1,4-dioxane (1 mL) and water (0.2 mL) was added ( R )-5-bromo- N- (1-methylpiperidin-3-yl)oxazolo[4,5- b ]pyridin-2-amine (0.080 g, 0.19 mmol, 0.92 eq), CsF (0.078 g, 0.51 mmol, 2.5 eq ) and XPhosPdG3 (0.035 g, 0.04 mmol, 0.2 eq), then the above reaction mixture was stirred at 95°C for 1 hour. The above reaction solution was diluted with water (100 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, then purified by preparative TLC (DCM: MeOH = 10:1, Rf = 0.1) , to afford the title compound (0.040 g, 38% yield) as a yellow solid. LCMS: m/z 494.2 [M+H] ⁺ , ESI pos. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ = 7.57 - 7.45 (m, 2H), 7.10 (d, 1H), 6.95 (d, 1H), 6.62 - 6.18 (m, 1H), 4.81 (s, 2H), 4.30 - 4.18 (m, 1H), 3.61 - 3.40 (m, 2H), 2.81 - 2.47 (m, 3H), 2.33 (s, 3H), 2.21 (s, 3H), 2.11 (s, 1H) , 1.96 - 1.81 (m, 2H), 1.72 - 1.59 (m, 2H), 0.90 - 0.76 (m, 2H), 0 (s, 9H).

step E. : 2- hydroxyl -4- methyl -3-[2-[[(3 R )-1- methyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ] Benzonitrile; 2,2,2- Trifluoroacetate

To ( R )-4-methyl-3-(2-((1-methylpiperidin-3-yl)amino)oxazolo[4,5-b]pyridin-5-yl)-2- To a solution of ((2-(trimethylsilyl)ethoxy)methoxy)benzonitrile (20 mg, 0.04 mmol, 1.0 eq) in DCM (2 mL) was added TFA (1.0 mL), then The above reaction mixture was stirred at 20°C for 1 hour. The above reaction mixture was concentrated under reduced pressure. The crude product was subjected to preparative HPLC (column: Phenomenex Synergi Polar-RP 100 × 25 mm × 4 um; condition: water (TFA)-MeCN; B: 22 at the beginning and B: 42 at the end; gradient time (minutes ): 7; 100% B hold time (min): 2, flow rate (mL/min) 25), and then the solvent was removed by lyophilization to give the title compound (4.6 mg, 24% yield) as a yellow solid. ¹ H NMR (CD ₃ OD _, 400 MHz) δ [ppm]: 7.83 (d, 1H), 7.49 (d, 1H), 7.17 (d, 1H), 6.98 (d, 1H), 4.33 - 3.84 (m, 2H), 3.63 - 3.44 (m, 1H), 3.18 - 2.84 (m, 5H), 2.32 - 2.23 (m, 1H), 2.21 (s, 3H), 2.18 - 2.09 (m, 1H), 2.02 - 1.86 ( m, 1H), 1.78 - 1.56 (m, 1H). Example 83 : 5- Chloro -3- methyl -2-[2-[(1- methyl -3- piperidinyl ) methyl ] oxazolo [4,5-b] pyridin -5- yl ] phenol

step A : 5- bromine -2-[(1- methyl -3- piperidinyl ) methyl ] zozolo [4,5-b] pyridine

2-Amino-6-bromopyridin-3-ol (50.0 mg, 0.26 mmol, 1.0 eq) and 2-(1-methyl-3-piperidinyl)acetic acid (46.0 mg, 0.29 mmol, 1.11 eq) was added to Eaton's reagent (1.0 mL) and the reaction was heated to 100 °C and stirred for 2 hours. The reaction was stirred overnight (16 hours). The reaction mixture was poured into a stirred Erlenmeyer flask containing saturated _NaHCO3 (50 mL), and when bubbling ceased, the solution was added to a separatory funnel containing DCM (30 mL) and extracted. The separated aqueous layer was further extracted with DCM (2 x 30 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (66.0 mg, 64% yield) as a dark brown solid. This compound was used in the next step without further purification. LCMS m/z: 310.0; 312.0 (Cl isotope) [M+H] ⁺ , ESI pos.

step B : 5- chlorine -3- methyl -2-[2-[(1- methyl -3- piperidinyl ) methyl ] zozolo [4,5- b ] pyridine -5- base ] phenol

5-Bromo-2-[(1-methyl-3-piperidinyl)methyl]oxazolo[4,5- b ]pyridine (66.0 mg, 0.17 mmol, 1.0 eq), (4-chloro- 2-Hydroxy-6-methyl-phenyl)boronic acid (CAS # 1207961-50-9, 36.0 mg, 0.19 mmol, 1.13 eq) and potassium carbonate (60.0 mg, 0.43 mmol, 2.55 eq) in water (0.5 mL) and 1,4-dioxane (2.5 mL) were bubbled with nitrogen for 5 minutes. Added [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (7.0 mg, 0.01 mmol, 0.06 eq), and the reaction mixture was heated to 90°C for 1.5 hours. The crude mixture was concentrated under reduced pressure and loaded onto silica. The crude reaction mixture was purified by column chromatography (silica gel, 24 g, 0% to 20% MeOH (0.7M NH ₃ ):EtOAc) to give the title compound (43.0 mg, 67% yield) as a light brown solid . LCMS m/z: 372.2; 374.0 (Cl isotope) [M+H] ⁺ , ESI pos. Example 84 : 4-[(3 R )-3-[[5-(4- Chloro -2- hydroxy -6- methyl - phenyl ) oxazolo [4,5-b] pyridin -2- yl ] Amino ]-1- piperidinyl ] butanoic acid methyl ester

step A : (3 R )-3-[[5-(4- chlorine -2- hydroxyl -6- methyl - Phenyl ) zozolo [4,5-b] pyridine -2- base ] Amino ] piperidine -1- Tertiary butyl formate

(4-Chloro-2-hydroxy-6-methyl-phenyl)boronic acid (CAS # 1207961-50-9, 524 mg, 2.81 mmol, 1.12 eq), (3 R )-3-[(5-bromo Zazolo[4,5-b]pyridin-2-yl)amino]piperidine-1-carboxylic acid tertiary butyl ester ( Example 75 , Step A ) (1.0 g, 2.52 mmol, 1.0 eq) and cesium carbonate ( 1715.0 mg, 5.26 mmol, 2.09 eq) in 1,4-dioxane (20 mL) and water (5 mL) were bubbled (N ₂ bubbled while sonicating) for 10 min. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (95.0 mg, 0.13 mmol, 0.05 eq) was added and the reaction mixture was heated to 80°C for 2 hours. The crude mixture was filtered through celite, rinsed with EtOAc (50 mL) and concentrated under reduced pressure. The residue was loaded onto Celite and purified by column chromatography (C ₁₈ , 10% to 100% MeCN: 10 mM NH ₄ HCO ₃ in water) to give the title compound (1.16 g, Yield 95%). LCMS m/z: 459.4; 461.4 (Cl isotope) [M+H] ⁺ , ESI pos.

step B : 5- chlorine -3- methyl -2-[2-[[(3 R )-3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ] Phenol; dihydrochloride

(3 R )-3-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino at 0°C To a stirred solution of ]piperidine-1-carboxylic acid tert-butyl ester (1.16 g, 2.53 mmol, 1.0 eq) in 1,4-dioxane (22 mL) was added 4M HCl in dioxane (2.5 mL, 10.0 mmol, 3.96 eq), and the reaction was warmed to room temperature. The reaction was diluted with 1,4-dioxane (5 mL) and MeOH (5 mL) and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound (1.23 g, 2.85 mmol, 95% yield) as a yellow solid. LCMS m/z: 359.3; 361.3 (Cl isotope) [M+H] ⁺ , ESI pos.

step C : 4-[(3 R )-3-[[5-(4- chlorine -2- hydroxyl -6- methyl - Phenyl ) zozolo [4,5-b] pyridine -2- base ] Amino ]-1- piperidinyl ] methyl butyrate

5-Chloro-3-methyl-2-[2-[[(3R)-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; disalt Acid salt (84.0 mg, 0.19 mmol, 1.0 eq) was dissolved in triethylamine (82.0 µL, 0.59 mmol, 3.02 eq) and DCM (2.5 mL) and stirred for 5 minutes. Acetic acid (56.0 µL, 0.98 mmol, 5.03 eq) was then added, and the mixture was stirred for 1 min before methyl 4-oxobutyrate (31.0 µL, 0.3 mmol, 1.52 eq) was added. The reaction mixture was stirred for 1 hour, then sodium triacetoxyborohydride (83.0 mg, 0.39 mmol, 2.01 eq) was added and the reaction mixture was stirred for 2 hours. Then methyl 4-oxobutyrate (21.0 µL, 0.2 mmol, 1.03 eq) was added, and after 0.5 h, sodium triacetyloxyborohydride (42.0 mg, 0.2 mmol, 1.02 eq) was added and incubated at room temperature Stir for 16 hours. The reaction mixture was quenched with HCl (1M, 100 µL), diluted with MeOH (5 ml) and stirred for 15 min. The reaction mixture was concentrated under reduced pressure to give a thick brown creamy solution. The solution was sonicated in THF (3 mL), and the resulting white solid was collected by filtration. The solid was taken up in DCM (10 mL) and K3PO4 (5 mL, 10% in water) and stirred vigorously for 10 min. The organic layer was separated, and the aqueous phase was further extracted with DCM (10 mL). The combined organic layers were dried over MgSO4, concentrated in vacuo, and purified by column chromatography (silica gel, 0% to 10% (0.7M NH3) MeOH/DCM) to give the title compound (30.0 mg , yield 33%). LCMS m/z: 459.2 [M+H] ⁺ , ESI pos. Example 85 : 3- Hydroxy -4-[2-[[ ( 3 R )-1-(2- hydroxyethyl )-3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridine- 5- yl ]-5- methyl - benzonitrile

The title compound was obtained as a dark brown foam, LCMS: m/z 394.3 [M+H] ⁺ , ESI pos, from 2-[( 3R )-3- [(5-Chloroxazolo[4,5- b ]pyridin-2-yl)amino]-1-piperidinyl]ethanol ( Example 52 , step 2 ) and (4-cyano-2-hydroxy- 6-Methyl-phenyl)boronic acid ( Example 25 , Step D ) was prepared initially. Example 86 : 3-[(3 R )-3-[[5-(4- Chloro -2- hydroxy -6- methyl - phenyl ) oxazolo [4,5-b] pyridin -2- yl ] Amino ]-1- piperidinyl ] propionic acid methyl ester

step A : 3-[(3 R )-3-[(5- bromozolo [4,5-b] pyridine -2- base ) Amino ]-1- piperidinyl ] Methyl propionate

To 5-bromo- N -[(3 R )-3-piperidinyl]oxazolo[4,5- b ]pyridin-2-amine; dihydrochloride (50.0 mg, 0.12 mmol, 1.0 eq) ( Example 75 , Step B ) To a stirred solution in MeCN (2.4 mL) was added cesium carbonate (310.0 mg, 0.95 mmol, 4.0 eq) and the reaction mixture was sonicated (2 min) and stirred for an additional 0.5 h. Then, methyl 3-bromopropionate (29.0 µL, 0.27 mmol, 1.12 eq) was added and the reaction was stirred for 1 hour. The reaction was then heated at 60°C for 2 hours. The reaction was then filtered through celite, concentrated under reduced pressure and loaded onto celite. The crude reaction mixture was purified by reverse phase column chromatography (dry load, C ₁₈ , 15% to 60% MeCN:H ₂ O (0.1% NH ₄ HCO ₃ )) to afford the title compound (60.0 mg , yield 53%). LCMS m/z: 383.2 ( ⁷⁹ Br); 385.2 ( ⁸¹ Br) [M+H] ⁺ , ES pos.

step B : 3-[(3 R )-3-[[5-(4- chlorine -2- hydroxyl -6- methyl - Phenyl ) zozolo [4,5- b ] pyridine -2- base ] Amino ]-1- piperidinyl ] Methyl propionate

Following the procedure outlined in Example 95 , the above 3-[(3 R )-3-[(5-bromozozolo[4,5-b]pyridin-2-yl)amino]-1-piperidinyl ] Methyl propionate was reacted with (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid ( CAS # 1207961-50-9 ) to give the title compound. LCMS m/z: 445.3; 447.3 (Cl isotope) [M+H] ⁺ , ESI pos. Example 87 : 5- Chloro -2-[2-[[6-( hydroxymethyl )-1- methyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridine -5- base ]-3- methyl - phenol ; 2,2,2- trifluoroacetic acid

step A : 5-(( Level three - Butoxycarbonyl ) Amino )-2-( Hydroxymethyl )-1- picoline -1- Onium (HI Salt )

To a solution of tert -butyl (6-(hydroxymethyl)pyridin-3-yl)carbamate (100 mg, 0.45 mmol, 1.0 eq) (CAS: 323578-38-7) in MeCN (2 mL) Iodomethane (189.9 mg, 1.34 mmol, 3.0 eq) was added. The mixture was stirred at 70 °C for 5 hours. The reaction mixture was cooled to 20 °C and concentrated in vacuo. The residue was triturated in ethyl acetate (3 ml) and stirred for 30 minutes. The suspension was filtered and the filter cake was washed with ethyl acetate (2 ml x 2) and driven off in vacuo to give the title compound (100.0 mg, 0.42 mmol, 94% yield, HI salt) as a yellow solid. LCMS: 239.0 [M+H] ⁺ , ESI pos.

step B : (6-( Hydroxymethyl )-1- Methylpiperidine -3- base ) Tertiary butyl carbamate

To 5-(( tertiary -butoxycarbonyl)amino)-2-(hydroxymethyl)-1-methylpyridin-1-ium (100.0 mg, 0.42 mmol, 1.0 eq) under N ₂ To a solution in methanol (5 mL) was added _PtO2 (10 mg, 0.04 mmol, 0.1 eq). The suspension was degassed under vacuum and flushed with _H2 several times. The mixture was then stirred at 25 °C for 48 hours under _H2 pressure of 2280 mmHg. The suspension was filtered, and the filter cake was washed with MeOH (20 mL x 3). The combined filtrates were concentrated in vacuo to afford the title compound (100 mg, 98% yield) as a yellow oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.98 (s, 1H), 3.95 - 3.85 (m, 1H), 3.84 - 3.77 (m, 1H), 3.64 (dd, 1H), ,3.00 (s, 3H), 2.84 - 2.80 (m, 1H), 2.75 - 2.70 (m, 2H), 2.05 - 1.84 (m, 2H), 1.83 - 1.60 (m, 2H), 1.44 (s, 9H).

step C : (5- Amino -1- Methylpiperidine -2- base ) Methanol (HCl Salt )

To (6-(hydroxymethyl)-1-methylpiperidin-3-yl) carbamate tert-butyl ester (100.0 mg, 0.41 mmol, 1.0 eq) in 1,4-dioxane (2 mL) To the mixture was added HCl/MeOH (2.0 mL). The mixture was stirred at 20 °C for 12 hours. Then, the reaction mixture was concentrated in vacuo to afford the title compound (70.0 mg, 0.39 mmol, 95% yield, HCl salt) as a yellow oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 4.10 -3.95 (m, 1H), 3.92 -3.80 (m, 2H), 3.75 -3.50 (m, 1H), 3.43 -3.37 (m, 1H), 3.25 - 3.15 (m, 1H), 3.05 (s, 3H), 2.12 - 2.08 (m, 2H), 2.05 - 1.98 (m, 2H) 1.85 - 1.75 (m, 1H).

step D. : (5-((5- bromozolo [4,5-b] pyridine -2- base ) Amino )-1- Methylpiperidine -2- base ) Methanol (TFA Salt )

To a solution of (5-amino-1-methylpiperidin-2-yl)methanol (55.72 mg, 0.31 mmol, 1.2 eq) in NMP (1 mL) was added DIPEA (99.46 mg, 0.77 mmol, 3.0 eq) and 5-bromo-2-chlorooxazolo[4,5-b]pyridine (60.0 mg, 0.26 mmol, 1.0 eq). The mixture was stirred at 20 °C for 1 hour. The residue was purified by column chromatography (C ₁₈ , 0.1% TFA in water/MeCN) to afford the title compound (90.0 mg, 77% yield, TFA salt) as a yellow oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.59 (d, 1H), 7.25 (d, 1H), 4.25 - 4.15 (m, 1H), 4.10 - 4.00 (m, 2H), 3.67 - 3.61 (m, 1H), 3.42 - 3.35 (m, 1H), 2.94 (s, 3H), 2.40 - 2.25 (m, 2H), 2.15 - 2.07 (m, 2H) 1.95 - 1.85 (m, 1H).

step E. : 5- chlorine -2-[2-[[6-( Hydroxymethyl )-1- methyl -3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl - phenol; 2,2,2- Trifluoroacetate

Under N ₂ , to (5-((5-bromozozolo[4,5-b]pyridin-2-yl)amino)-1-methylpiperidin-2-yl)methanol (80.0 mg, 0.18 mmol, 1.0 eq) and (4-chloro-2-hydroxy-6-methylphenyl)boronic acid (49.1 mg, 0.26 mmol, 1.5 eq) in 1,4-dioxane (3 mL) and water (0.6 mL) K ₂ CO ₃ (72.86 mg, 0.53 mmol, 3.0 eq) and XPhos Pd G3 (14.9 mg, 0.02 mmol, 0.1 eq) were added to the solution in . The mixture was stirred at 80 °C under _N2 for 2 h. Then, the mixture was cooled to 20 °C and concentrated in vacuo. The residue was dissolved in MeOH (2 ml), and analyzed by preparative HPLC (column: Phenomenex Synergi Polar-RP 100 × 25 mm × 4 um, conditions: water (TFA)-MeCN, B: 22 at the beginning; end Time B: 42; Gradient time (min): 7; 100% B hold time (min): 2; Flow rate (ml/min): 25), to obtain the title compound as a yellow solid (58.3 mg, yield 62%, TFA salt). LCMS: m/z 403.2 [M+H] ⁺ , ESI pos. Example 88 : 5- Chloro -2-[2-[(4- isopropylmorpholin -2- yl ) methyl ] oxazolo [4,5-b] pyridin -5- yl ]-3- methyl -phenol ; formic acid

step A : 5- bromine -2-[(4- Isopropylmorpholine -2- base ) methyl ] zozolo [4,5-b] pyridine

At room temperature, 2-amino-6-bromopyridin-3-ol (50.0 mg, 0.26 mmol, 1.0 eq) and 2-(4-isopropylmorpholin-2-yl)acetic acid (54.0 mg, 0.29 mmol , 1.09 eq) was added to Eaton's reagent (1.0 mL), and the reaction was heated to 100 °C and stirred overnight. The reaction mixture was poured into a stirred Erlenmeyer flask containing saturated _NaHCO3 (50 mL), and when bubbling ceased, the solution was added to a separatory funnel containing DCM (30 mL) and extracted. The separated aqueous layer was further extracted with DCM (2 x 30 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (84.0 mg, 71% yield) as a dark brown solid. LCMS m/z: 340.0; 342.0 (Cl isotope) [M+H] ⁺ , ESI pos.

step B : 5- chlorine -2-[2-[(4- Isopropylmorpholine -2- base ) methyl ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl - Phenol; Formic acid

5-Bromo-2-[(4-isopropylmorpholin-2-yl)methyl]oxazolo[4,5-b]pyridine (84.0 mg, 0.19 mmol, 1.0 eq), (4-chloro -2-Hydroxy-6-methyl-phenyl)boronic acid (39.0 mg, 0.21 mmol, 1.12 eq) and potassium carbonate (65.0 mg, 0.47 mmol, 2.51 eq) in water (0.5 mL) and 1,4-diox The solution in alkanes (2 mL) was bubbled with N2 for 10 min. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (7.0 mg, 0.01 mmol, 0.05 eq) was added and the reaction mixture was heated to 90°C for 70 minutes. The reaction was stirred overnight. The crude mixture was concentrated under reduced pressure and purified by column chromatography (silica gel, 0% to 12% MeOH (0.7M _NH3 ):EtOAc) to give a product containing co-eluted starting material. A second reverse phase column (dry loaded Celite; C ₁₈ , 10% to 60% MeCN (0.1% formic acid): 0.1% formic acid in water) afforded the title compound (25.0 mg, Yield 28%). LCMS m/z: 402.2; 404.2 (Cl isotope) [M+H] ⁺ , ESI pos. Example 89 : 3- Methyl -2-[2-[[(3 R )-1- methyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridin -5- yl ] -5- methylsulfonyl - phenol; 2,2,2- trifluoroacetic acid

step A : 3- methyl -5-( Methylsulfonyl ) phenol

The device was dried by heating with an air heater under vacuum. To a mixture of 3-bromo-5-methyl-phenol (4500.0 mg, 24.06 mmol, 1.0 eq CAS: 74204-00-5) in DMSO (45 mL) was added CuI (1142.86 mg, 6.02 mmol, 0.25 eq) , L -proline (1385.0 mg, 12.03 mmol, 0.5 eq), sodium hydroxide (481.17 mg, 12.03 mmol, 0.5 eq) and sodium methanesulfinate (7362.5 mg, 72.2 mmol, 3.0 eq), and the mixture Stir at 120 °C for 3 h under _N2 . The reaction mixture was quenched with water (20 mL), then adjusted to pH = 8 by 1N HCl solution, then extracted by EtOAc (30 mL × 3), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was decompressed Concentrate. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 1/1) to obtain the title compound (3000 mg, yield 67%) as yellow oil. ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.21 (s, 1H), 7.11 (s, 1H), 6.92 (s, 1H), 3.06 (s, 3H), 2.36 (s, 3H).

step B : 2- iodine -3- methyl -5- Methylsulfonyl - phenol

To a mixture of 3-methyl-5-methylsulfonyl-phenol (3.0 g, 16.11 mmol, 1.0 eq) in toluene (25 mL) at 0 °C was added NaH (1.29 g, 32.22 mmol, 2.0 eq 60 %), and the mixture was stirred at 0°C for 10 minutes, then I ₂ (3.26 g, 12.89 mmol, 0.8 eq) was added to the mixture, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched with water, then adjusted to pH = 6 by 1N HCl, then extracted by EtOAc (20 mL × 3), washed with brine (20 mL × 2), dried over _{anhydrous Na2SO4} , filtered, And the filtrate was concentrated to give a yellow solid. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10:0 to 1:1) to give the title compound (1.3 g, yield 26%) as a yellow solid. LCMS: m/z 312.9 [M+H] ⁺ , ESI pos.

step C : 3- methyl -5- Methylsulfonyl -2-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base ) Phenol and (2- hydroxyl -6- methyl -4- Methylsulfonyl - Phenyl ) boric acid

To 2-iodo-3-methyl-5-methylsulfonyl-phenol (400.0 mg, 1.28 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'- Mixture of octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.62 g, 6.41 mmol, 5.0 eq) in 1,4-dioxane (8 mL) KOAc (377.3 mg, 3.84 mmol, 3.0 eq) and Pd(dppf)Cl ₂ (93.7 mg, 0.13 mmol, 0.1 eq) were added, and the mixture was stirred at 95°C for 4 hours. The mixture was cooled to 25°C. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (C ₁₈ , 0.1% TFA in water/MeCN) to afford the title compound (100 mg, 25% yield) as a yellow solid. LCMS: m/z 313.3 [M+H] ⁺ , ESI pos.

step D. : 3- methyl -2-[2-[[(3 R )-1- methyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-5- Methylsulfonyl - phenol; 2,2,2- Trifluoroacetate

3-methyl-5-methylsulfonyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane at 25°C under N ₂ -2-yl)phenol (50.0 mg, 0.16 mmol, 1.0 eq), 5-bromo- N -[( 3R )-1-methyl-3-piperidinyl]oxazolo[4,5-b] Pyridin-2-amine; 2,2,2-trifluoroacetic acid ( Example 30 , Step H ) (68.1 mg, 0.16 mmol, 1.0 eq), K ₂ CO ₃ (66.31 mg, 0.48 mmol, 3.0 eq) in 1, To a solution in 4-dioxane (1 mL)/water (0.2 mL) was added Pd(dppf)Cl ₂ (11.71 mg, 0.02 mmol, 0.1 eq), then stirred at 95°C for 4 hours. The mixture was then cooled to 25°C, filtered, and the filtrate concentrated under vacuum. The crude product was purified by C18 column chromatography (20 g, 0.1% TFA in water/MeCN) to afford the title compound (35.9 mg, 42% yield) as a white solid. LCMS: m/z 417.1 [M+H] ⁺ , ESI pos. Example 90 : 5- Chloro -2-[2-[2- methoxyethyl -[(3 R )-1- methyl -3- piperidinyl ] amino ] oxazolo [4,5-b ] pyridin -5- yl ]-3- methyl - phenol; formic acid

step A : 5- chlorine - N -(2- Methoxyethyl )-N-[(3 R )-1- methyl -3- piperidinyl ] zozolo [4,5-b] pyridine -2- amine

5-Chloro- N -[( 3R )-1-methyl-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine ( Example 15 , Step 1) (200 mg, 0.75 mmol, 1.0 eq) in DMF (2 mL) was cooled to 0 °C and sodium hydride (60% in mineral oil, 45 mg, 1.12 mmol, 1.5 eq) was added. The mixture was warmed to room temperature and stirred for 5 minutes. 2-Bromoethylmethyl ether (CAS # 6482-24-2, 0.08 mL, 0.9 mmol, 1.2 eq) was then added to the reaction mixture, which was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL) and EtOAc (10 mL). The phases were separated and the aqueous phase was extracted with additional EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (2 x 10 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (12 g, 0% to 10% (0.7 M ammonia/MeOH)/DCM) to afford the title compound (65.0 mg, 25% yield) as a colorless gum. LCMS m/z 325.3 [M+H] ⁺ , ESI pos.

step B : 5- chlorine -2-[2-[2- Methoxyethyl -[(3 R )-1- methyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- methyl - Phenol; Formic acid

5-Chloro- N- (2-methoxyethyl) -N -[(3 R )-1-methyl-3-piperidinyl]oxazolo[4,5-b]pyridine-2- Amine (65.0 mg, 0.2 mmol, 1.0 eq), (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (41.0 mg, 0.22 mmol, 1.1 eq), 1,1'-bis(diphenyl phosphino)ferrocenepalladium(II) dichloride toluene adduct (8.2 mg, 0.01 mmol, 0.05 eq) and potassium carbonate (55.3 mg, 0.4 mmol, 2.0 eq) in 1,4-dioxane ( 1.6 mL) and water (0.4 mL) was degassed with _N2 for about 5 minutes, then heated to 80 °C for 4 hours. The mixture was cooled to room temperature, then XPhos Pd G3 (8.5 mg, 0.01 mmol, 0.05 eq) was added, and the reaction mixture was degassed with N ₂ for about 5 minutes and then heated to 80° C. for 3 hours. The reaction mixture was cooled to room temperature and stirred at this temperature for 2 days. The reaction mixture was diluted with brine (10 mL) and EtOAc (10 mL), then the layers were separated and the aqueous layer was further extracted with EtOAc (2 x 10 mL). The combined organic phases were concentrated in vacuo and the crude product was purified by silica gel chromatography (4 g, 0% to 10% (( _0.7M NH in MeOH)/DCM)) followed by RP chromatography (12 g, 5% to 55% (0.1% formic acid in MeCN)/(0.1% formic acid in water)) to afford the title compound (26.0 mg, 26% yield) as a pale yellow solid. LCMS m/z 431.4 [M+H] ⁺ , ESI pos. Example 91 : 2-[2-[[(3 R )-1- ethylazol -3- yl ] amino ] oxazolo [4,5- b ] pyridin - 5- yl ]-3- methyl -5-( Trifluoromethyl ) phenol

step 1 : N -[(3 R )-1- ethyl nitrogen 𠰢 -3- base ] Tertiary butyl carbamate

The title compound was obtained as a pale yellow oil, LCMS: m/z 243.4 [M+H] ⁺ , ESI pos, from N -[( 3R )-nitrogen The preparation started with tertiary-butyl-3-yl]carbamate (CAS # 1354351-56-6) and iodoethane (CAS # 75-03-6).

step 2 : 5- chlorine - N -[(3 R )-1- ethyl nitrogen 𠰢 -3- base ] zozolo [4,5-b] pyridine -2- amine

The title compound was obtained as a pale yellow solid, LCMS: m/z 295.3 [M+H] ⁺ , ESI pos, from N -[( 3R )-1- Ethylazolam-3-yl]carbamate tert-butyl ester ( Example 91 , Step 1 ) and 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (CAS # 1783370- 92-2) Start preparation.

step 3 : 2-[2-[[(3 R )-1- ethyl nitrogen 𠰢 -3- base ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

The title compound was obtained as a yellow foam, LCMS: m/z 435.3 [M+H] ⁺ , ESI pos, from 5-chloro- N -[( 3R ) using chemistry similar to that described in step 2 of Example 14. -1-Ethylazol-3-yl]oxazolo[4,5-b]pyridin-2-amine ( Example 91 , step 1 ) and 3-methyl-2-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol ( CAS # 2557358-38-8 ) was prepared initially. Example 92 : 5- Chloro -2-[2-[(3- hydroxycyclobutyl ) methylamino ] oxazolo [4,5-b] pyridin -5- yl ]-3- methyl - phenol

step A : 3-( Aminomethyl ) Cyclobutanol; hydrochloride

To a solution of trans-3-(Boc-aminomethyl)cyclobutanol (100 mg, 0.5 mmol, 1.0 eq) in 1,4-dioxane (0.5 mL) was added HCl/dioxane ( 0.5 mL, 2.0 mmol, 4.03 eq). The mixture was stirred at 20°C for 2 hours. Then, the mixture was concentrated under reduced pressure to give the title compound (68.0 mg, 99% yield) as a white solid.

step B : 3-[[(5- bromozolo [4,5-b] pyridine -2- base ) Amino ] methyl ] Cyclobutanol; 2,2,2- Trifluoro - Acetic acid

To a solution of 3-(aminomethyl)cyclobutanol; hydrochloride (68.0 mg, 0.49 mmol, 1.0 eq) and DIPEA (0.26 mL, 1.48 mmol, 3.0 eq) in MeCN (7 mL) was divided into five 5-Bromo-2-chloro-oxazolo[4,5-b]pyridine (115.4 mg, 0.49 mmol, 1.0 eq) was added in batches, and the mixture was stirred at 20°C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography (C ₁₈ , 0.1% TFA in water/MeCN) to give the title compound ( 45.0 mg, yield 31%). LCMS: m/z 298.1 [M+H] ⁺ , ESI pos.

step C : 5- chlorine -2-[2-[(3- Hydroxycyclobutyl ) Methylamino ] zozolo [4,5-b] pyridine -5- base ]-3- methyl - phenol

Under nitrogen gas, to 3-[[(5-bromozozolo[4,5-b]pyridin-2-yl)amino]methyl]cyclobutanol; 2,2,2-trifluoroacetic acid ( 20.0 mg, 0.07 mmol, 1.0 eq) and (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (18.76 mg, 0.1 mmol, 1.5 eq) in 1,4-dioxane (2 mL) and water (0.4 mL) were added CsF (40.8 mg, 0.27 mmol, 4.0 eq) and XPhosPdG3 (5.68 mg, 0.01 mmol, 0.1 eq). The mixture was stirred at 90 °C for 2 hours. Then, the reaction mixture was cooled to 25 °C, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (C ₁₈ , 0.1% TFA in water/MeCN) to afford the title compound (14.5 mg, 58% yield) as a white solid. LCMS: m/z 360.0 [M+H] ⁺ , ESI pos. Example 93 : 5- Chloro -2-[2-[[(3 R )-1-(2- hydroxyethyl )-3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridine- 5- yl ]-3- methyl - phenol

The title compound was obtained as an off-white foam, LCMS: m /z 403.2 [M+ H ] ⁺ , ESI pos, from 2-[( 3R )-3-[(5 -Chlorozozo[4,5- b ]pyridin-2-yl)amino]-1-piperidinyl]ethanol ( Example 52 , step 2 ) and (4-chloro-2-hydroxyl-6-methyl -Phenyl)boronic acid ( CAS# 1207961-50-9 ) was prepared initially. Example 94 : 5- Chloro -3-( hydroxymethyl )-2-[2-[[(3R)-1- methyl -3- piperidinyl ] amino ] oxazolo [4,5-b] Pyridin -5- yl ] phenol

step A : 5- chlorine -3- hydroxyl -2- iodine - Benzaldehyde

To a mixture of 3-chloro-5-hydroxybenzaldehyde (CAS # 1829-33-0, 8.1 g, 51.7 mmol, 1.0 eq) in DMF (81 mL) was added portionwise NaH ( 2.48 g, 103.47 mmol, 2.0 eq, 60%), stirred for 30 minutes, then added I ₂ (13.1 g, 51.7 mmol, 1.0 eq) in portions and stirred at 25°C for 15.5 hours. The mixture was poured into a molar aqueous hydrochloric acid solution (100 ml) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 5:1), and was purified by column chromatography (C ₁₈ , 20 g, 0.1% NH ₃ ·H ₂ O solution in water/MeCN) was repurified to give the title compound (730 mg, 4% yield) as a light green solid. LCMS: m/z 280.9 [MH] ^- , ESI neg.

step B : 5- chlorine -2- iodine -3-(2- Trimethylsilylethoxymethoxy ) Benzaldehyde

A mixture of Cs ₂ CO ₃ (865.13 mg, 2.66 mmol, 1.5 eq) and 5-chloro-3-hydroxy-2-iodo-benzaldehyde (500.0 mg, 1.77 mmol, 1.0 eq) in DMF (10 mL) was decomposed gas, and purged with N ₂ three times, and stirred for another 30 minutes. Then, a batch of SEM-Cl (442.7 mg, 2.66 mmol, 1.5 eq) was added to the mixture. The mixture was stirred at 25°C for 2 hours. Then, the mixture was poured into water (50 mL), and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1:0 to 10:1) to obtain the title compound (500 mg, yield 68%) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.02 (s, 1H), 7.48 (d, 1H), 7.38 (d, 1H), 5.46 (s, 2H), 3.76 (t, 2H ), 0.89 (t, 2H), -0.04 (s, 9H).

step C : [5- chlorine -2- iodine -3-(2- Trimethylsilylethoxymethoxy ) Phenyl ] Methanol

Sodium borohydride (55.0 mg, 1.45 mmol, 1.2 eq) was added in small portions to 5-chloro-2-iodo-3-(2-trimethylsilylethoxymethoxy)benzaldehyde (500.0 mg, 1.21 mmol, 1.0 eq) in methanol (5 mL) and water (0.5 mL). The mixture was stirred at 25°C for 3 hours. The mixture was poured into water (15 ml), and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (470 mg, 94% yield) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.13 (s, 1H), 7.09 (d, 1H), 5.60 (t, 1H), 5.36 (s, 2H), 4.42 - 4.37 (m , 2H), 3.73 (t, 2H), 0.92 - 0.85 (m, 2H), -0.02-0.05 (m, 9H).

step D. : [4- chlorine -2-( Hydroxymethyl )-6-(2- Trimethylsilylethoxymethoxy ) Phenyl ] boric acid

[5-Chloro-2-iodo-3-(2-trimethylsilylethoxymethoxy)phenyl]methanol (60.0 mg, 0.14 mmol, 1.0 eq) and bis(pinacle) A mixture of boron (183.69 mg, 0.72 mmol, 5.0 eq) in 1,4-dioxane (150 mL) was degassed and purged with nitrogen three times, and a batch of KOAc (42.6 mg, 0.43 mmol, 3.0 eq) , Pd(dppf)Cl ₂ (10.6 mg, 0.01 mmol, 0.1 eq) was added to the mixture. The mixture was heated at 90 °C for 2 hours under microwave irradiation. The mixture was purified by column chromatography (C ₁₈ , 0.1% TFA in water/MeCN) to afford the title compound (40.0 mg, 0.1 mmol, 67% yield) as a dark brown oil. ¹ H NMR (400 MHz, CD ₃ OD) δ [ppm]: 6.99 (s, 1H), 6.94 (s, 1H), 5.29 (s, 1H), 5.22 (s, 1H), 4.55 (s, 2H) , 3.81 - 3.71 (m, 2H), 0.93 (t, 2H), 0.01 (s, 9H).

step E. : [5- chlorine -2-[2-[[(3 R )-1- methyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3-(2- Trimethylsilylethoxymethoxy ) Phenyl ] Methanol

K ₂ CO ₃ (41.5 mg, 0.3 mmol, 2.5 eq), 5-bromo- N -[(3 R )-1-methyl-3-piperidinyl]oxazolo[4,5-b]pyridine -2-amine; 2,2,2-trifluoroacetic acid (76.7 mg, 0.18 mmol, 1.5 eq) and [4-chloro-2-(hydroxymethyl)-6-(2-trimethylsilylethoxy A mixture of (methoxy)phenyl]boronic acid (40.0 mg, 0.12 mmol, 1.0 eq) in 1,4-dioxane (1 mL) and water (0.2 mL) was degassed, purged with nitrogen three times, and then XPhos Pd G3 (10.11 mg, 0.01 mmol, 0.1 eq) was added to the mixture. The mixture was heated at 95°C for 2 hours. The mixture was concentrated under reduced pressure and purified by column chromatography (C ₁₈ , 0.1% NH ₃ ·H ₂ O in water/MeCN) to give the title compound as a red oil (27.0 mg, yield 43%). ¹ H NMR (400 MHz, CD ₃ OD) δ [ppm]: 7.80 (d, 1H), 7.28 (s, 1H), 7.23 (s, 1H), 7.13 (d, 1H), 5.13 (s, 2H) , 4.34 (s, 1H), 4.15 - 4.09 (m, 1H), 3.88 (d, 1H), 3.57 (t, 2H), 3.54 - 3.47 (m, 1H), 2.94 (s, 3H), 2.32 - 2.19 (m, 1H), 2.18 (br s, 1H), 2.03 (s, 1H), 1.93 - 1.84 (m, 1H), 1.72 - 1.64 (m, 1H), 1.42 - 1.27 (m, 1H), 0.85 ( t, 2H), -0.05 (s, 9H).

step f : 5- chlorine -3-( Hydroxymethyl )-2-[2-[[(3 R )-1- methyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ] phenol

[5-Chloro-2-[2-[[(3 R )-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3 -(2-Trimethylsilylethoxymethoxy)phenyl]methanol (14.0 mg, 0.03 mmol, 1.0 eq) and TFA (0.26 mL, 3.49 mmol, 129.4 eq) in DCM (1 mL) The solution was stirred at 25°C for 2 hours. After removal of solvent, the residue was purified by column chromatography (C ₁₈ , 0.1% TFA in water/MeCN) to afford the title compound (7.25 mg, 0.01 mmol, 69% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ [ppm]: 7.87 (d, 1H), 7.27 (d, 1H), 7.10 (s, 1H), 6.90 (s, 1H), 4.50 - 4.32 (m, 2H), 4.29 - 4.09 (m, 1H), 3.98 - 3.79 (m, 1H), 3.64 - 3.38 (m, 1H), 3.15 - 3.05 (m, 1H), 2.94 ( s, 5H), 2.29 - 2.08 ( m, 1H), 2.03 - 1.82 (m, 2H), 1.79 - 1.59 (m, 1H). Example 95 : 5- Chloro -2-[2-[[(3 R )-1-(3- hydroxypropyl ) -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridine- 5- yl ]-3- methyl - phenol

step A : 3-[(3 R )-3-[(5- bromozolo [4,5-b] pyridine -2- base ) Amino ]-1- piperidinyl ] C -1- alcohol

To 5-bromo- N -[( 3R )-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine; Dihydrochloride ( Example 75 , Step B ) (50.0 mg, 0.12 mmol, 1.0 eq) to a stirred solution in 1,4-dioxane (1.2 mL) was added N,N -diisopropylethylamine (200 µL, 1.15 mmol, 9.66 eq) and 3-bromo-1 -propanol (12.0 µL, 0.13 mmol, 1.12 eq), and the reaction was stirred at 100°C for 18 hours. The reaction was cooled to room temperature and diluted with DCM (5 mL) and MeOH (1 mL), then concentrated onto silica under reduced pressure. The crude reaction mixture was purified by column chromatography (silica gel, 0% to 10% MeOH (0.7 M NH ₃ ):EtOAc) to afford the title compound (22 mg, 60% yield) as a light yellow oil. LCMS m/z 355.2.1; 357.2 (Br isotope) [M+H] ⁺ , ESI pos.

step B : 5- chlorine -2-[2-[[(3 R )-1-(3- Hydroxypropyl )-3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- methyl - phenol

3-[(3 R )-3-[(5-Bromozozolo[4,5-b]pyridin-2-yl)amino]-1-piperidinyl]propan-1-ol (55.0 mg , 0.15 mmol, 1.0 eq), (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (33.0 mg, 0.18 mmol, 1.14 eq) and potassium carbonate (43.0 mg, 0.31 mmol, 2.01 eq) in A solution of 1,4-dioxane (3 mL) and water (1 mL) was bubbled (with N ₂ while being sonicated) for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (7.0 mg, 0.01 mmol, 0.06 eq) was added and the reaction mixture was heated to 90°C for 16 hours. The crude mixture was concentrated under reduced pressure and purified by column chromatography (silica gel, 0% to 50% MeOH:EtOAc) to afford the title compound (39.0 mg, 59% yield) as a dark brown solid. LCMS m/z m/z 417.4 [M+H] ⁺ , ESI pos. Example 96 : 5- Chloro -2-[2-[[(3 R )-1-(3- methoxypropyl )-3- piperidinyl ] amino ] oxazolo [4,5-b] Pyridin -5- yl ]-3- methyl - phenol

step A : 5- bromine - N -[(3R)-1-(3- Methoxypropyl )-3- piperidinyl ] zozolo [4,5-b] pyridine -2- amine

To 5-bromo- N -[(3 R )-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine; dihydrochloride (50.0 mg, 0.12 mmol, 1.0 eq) ( Example 73 , Step 3 ) To a stirred solution in MeCN (2.4 mL) was added cesium carbonate (315.0 mg, 0.97 mmol, 4.07 eq) and the reaction mixture was sonicated (2 min) and stirred for an additional 0.5 h. Then, 1-bromo-3-methoxypropane (29.0 µL, 0.26 mmol, 1.1 eq) was added and the reaction was stirred for 1 hour. The reaction was then heated at 60 °C overnight (16 hours). The reaction was filtered through celite, concentrated under reduced pressure and loaded onto celite. The crude reaction mixture was purified by reverse phase column chromatography (dry load, C18, 40 g, 5% to 20% MeCN: _H2O (0.1% _HCO2H ) to afford the title compound as a colorless amorphous solid ( 34.0 mg, yield 38%).

step B : 5- chlorine -2-[2-[[(3 R )-1-(3- Methoxypropyl )-3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl - phenol

Following the experimental procedure outlined above ( Example 95 ), the above 5-bromo- N -[( 3R )-1-(3-methoxypropyl)-3-piperidinyl]oxazolo[4 ,5-b]pyridin-2-amine (34 mg, 0.09 mmol, 1.0 eq) was reacted with (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (21 mg, 1.2 mmol, 1.2 eq) , to obtain the title compound (18.6 mg, yield 46%). LCMS m/z 431.4; 433.4 (Cl isotope) [M+H] ⁺ , ESI pos. Example 97 : 5- Chloro -3- methyl -2-[2-[[(3 R )-1-(2- hydroxypropyl )-3- piperidinyl ] amino ] oxazolo [4,5 -b] pyridin -5- yl ] phenol

step A : 1-[(3 R )-3-[(5- bromozolo [4,5- b ] pyridine -2- base ) Amino ]-1- piperidinyl ] C -2- alcohol

5-Bromo- N -[( 3R )-3-piperidinyl]oxazolo[4,5- b ]pyridin-2-amine ( Example 75 , Step B ) (159 mg, 0.41 mmol, 1.0 eq ) ( Example 75 , step 3 ) and potassium carbonate (281 mg, 2.0 mmol, 5.0 eq) in DMF (2 mL) was stirred for 5 minutes, then 1-chloro-2-propanol (76.9 mg, 0.81 mmol , 2.0 eq) in DMF (0.5 mL). The reaction mixture was heated at 60°C for 16 hours. Then, the reaction mixture was heated up to 90 °C and stirring was continued for 5 hours. Finally, the reaction mixture was heated up to 110 °C for 16 hours. Then, the reaction mixture was cooled to room temperature and kept at this temperature for 5 days. The reaction mixture was diluted with water (10 mL), and 1M aqueous HCl was added until pH 7 was reached. EtOAc (10 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 10 mL), then the combined organic phases were concentrated in vacuo. The crude product was purified by chromatography (silica gel, column, 0% to 10% (MeOH/DCM)), then the column was rinsed with 20% ( _0.7M NH in MeOH)/DCM to give a brown oil The title compound (21.0 mg, 18% yield). LCMS m/z: 355.2; 357.1 (Br isotope) [M+H]+, ESI pos.

step B : 5- chlorine -3- methyl -2-[2-[[(3 R )-1-(2- Hydroxypropyl )-3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ] phenol

Following the experimental procedure outlined above ( Example 95 ), the above 1-[( 3R )-3-[(5-bromooxazolo[4,5-b]pyridin-2-yl)amino]- 1-piperidinyl]propan-2-ol (21.0 mg, 0.05 mmol, 1.0 eq) and (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (11.6 mg, 0.06 mmol, 1.2 eq) Reacted to give the title compound (8.0 mg, 33% yield). LCMS m/z 417.3 [M+H] ⁺ , ESI pos. Example 98 : 5- Chloro -2-[2-[2- hydroxyethyl -[(3 R )-1- methyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridine -5- yl ]-3- methyl - phenol

step A : 5- bromine -N-[2-[ Level three - Butyl ( Dimethyl ) Silyl ] Oxyethyl ]-N-[(3R)-1- methyl -3- piperidinyl ]- zozolo [4,5-b] pyridine -2- amine

5-Bromo-N-[(3R)-1-methyl-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine ( Example 30 , Step H ) (120 mg, 0.39 mmol, 1.0 eq) in DMF (2 mL) was cooled to 0 °C and sodium hydride (60% in mineral oil, 23.1 mg, 0.58 mmol, 1.5 eq) was added. The mixture was warmed to room temperature and stirred for 5 minutes. Then (2-bromoethoxy) -tertiary -butyldimethylsilane (CAS # 86864-60-0, 0.1 mL, 0.46 mmol, 1.2 eq) was added and stirred at room temperature for 16 hours. The reaction mixture was cooled to 0 °C and sodium hydride (60% in mineral oil, 7.7 mg, 0.19 mmol, 0.5 eq) was added, then stirred at room temperature for 2 hours. The reaction was quenched with water (2 mL), diluted with 10% aqueous LiCl (10 mL) and EtOAc (3 mL), and the layers were separated. The organic layer was washed with 10% aqueous LiCl (2 x 10 mL), and concentrated in vacuo. The crude product was purified by chromatography (silica gel, 5% to 10% MeOH/DCM) to afford the title compound (76 mg, 40% yield) as a pale yellow solid. LCMS m/z 469.3; 471.3 (Br isotope) [M+H] ⁺ , ESI pos.

step B : 2-[2-[2-[ Level three - Butyl ( Dimethyl ) Silyl ] Oxyethyl -[(3 R )-1- methyl -3- piperidinyl ] Amino ]- zozolo [4,5-b] pyridine -5- base ]-5- chlorine -3- methyl - phenol

5-Bromo- N- [2-[tertiary-butyl(dimethyl)silyl]oxyethyl] -N -[(3 R )-1-methyl-3-piperidinyl]㗁Azolo[4,5-b]pyridin-2-amine (76.0 mg, 0.16 mmol, 1.0 eq), (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (58.0 mg, 0.31 mmol, 1.92 eq) and potassium carbonate (47.0 mg, 0.34 mmol, 2.1 eq) in 1,4-dioxane (3 mL) and water (1 mL) were bubbled (while ultrasonically treated with N ₂ bubbles) for 10 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (7.0 mg, 0.01 mmol, 0.06 eq) was added and the reaction mixture was heated to 90°C for 1 hour. The reaction was diluted with 50 vol% brine (50 mL) and EtOAc (50 mL), and the layers were separated. The aqueous layer was further extracted with EtOAc (2 x 50 mL), the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography (40 g, 0% to 10% MeOH (0.7M NH ₃ )/EtOAc) to afford the title compound (91.0 mg, 85% yield) as a pale yellow solid. LCMS m/z 531.4 [M+H] ⁺ , ESI pos.

step C : 5- chlorine -2-[2-[2- Hydroxyethyl -[(3 R )-1- methyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- methyl - phenol

To 2-[2-[2-[tertiary-butyl(dimethyl)silyl]oxyethyl-[(3 R )-1-methyl-3-piperidinyl]amino]oxazole [4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol (79.0 mg, 0.15 mmol, 1.0 eq) in 1,4-dioxane (2 mL) and methanol ( 200 µL) was added 4M HCl in dioxane (750.0 µL, 3.0 mmol, 20.2 eq) and the reaction mixture was stirred at room temperature for 45 min. The reaction was concentrated to dryness to afford 68 mg of a brown solid. 40 mg of the isolated material was dissolved in MeOH (approximately 2 mL) and applied to the SCX column. The cartridge was washed with MeOH (50 mL), then the product was eluted with 7M _NH3 in MeOH. The solvent was concentrated in vacuo, and the resulting solid was dried in a vacuum desiccator at 45°C to give the title compound (28.0 mg, 43% yield) as a light brown solid. LCMS m/z 417.3 [M+H] ⁺ , ESI pos. Example 99a : 5- Chloro -2-[2-[[( 3S , 4R )-1- ethyl -4- fluoro -3- piperidinyl ] amino ] oxazolo [4,5-b] Pyridin -5- yl ]-3- methyl - phenol

step A : relative cis -3-[(5- Chlorazolo [4,5-b] pyridine -2- base ) Amino ]-4- fluorine - piperidine -1- Tertiary butyl formate

According to GP1 , 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (150 mg, 733 µmol, 1.0 eq) was mixed with relative cis -3-amino-4-fluoro- Tert-butyl piperidine-1-carboxylate (201.9 mg, 879.1 µmol, 1.2 eq) was reacted in a sealed tube at 140°C under MW conditions for 1 hour, then continued stirring at 140°C for 2 days. Then, N,N -diisopropylethylamine (142.0 mg, 188 µL, 1.1 mmol, 1.5 eq) and relative cis -3-amino-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester (202.0 mg, 879 µmol, 1.2 eq), and the reaction was stirred at 150°C for 1 day. After work-up and flash chromatography (silica gel, gradient: 0% to 50% EtOAc in heptane), the title compound was obtained as an orange viscous oil (50.2 mg, 18%). LCMS: m/z 371.2 [M+H] ⁺ , ESI pos.

step B : 5- chlorine -2-[2-[[(3 S ,4 R )-1- Ethyl -4- fluorine -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- methyl - Phenol and 5- chlorine -2-[2-[[(3 R ,4 S )-1- Ethyl -4- fluorine -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- methyl - phenol

According to GP2a , relative cis -3-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]-4-fluoro-piperidine-1-carboxylic acid tertiary butyl ester ( 175 mg, 353.95 µmol, 1.0 eq) was reacted with (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (118.8 mg, 637 µmol, 1.8 eq). The crude product was purified by flash chromatography (Gradient: 0% to 50% EtOAc in heptane) to give relative cis -3-[[5-(4-chloro-2-hydroxyl as a yellow viscous oil -6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-4-fluoro-piperidine-1-carboxylic acid tertiary butyl ester (147 mg, 80%) . LCMS: m/z 477.3 [M+H] ⁺ , ESI pos.

Two fractions were obtained after chiral SFC separation (column: Chiral IK, 5 µm, 250 × 20 mm, 80 mL flow, 100 bar, 28% MeOH). First elute 5-chloro-2-[2-[[(3S,4R)-1-ethyl-4-fluoro-3-piperidinyl]amino]oxazolo[4,5-b]pyridine- 5-yl]-3-methyl-phenol (retention time 3.06; 53.4 mg, 34% yield), second eluate 5-chloro-2-[2-[[(3R,4S)-1- Base-4-fluoro-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol (retention time 3.92; 48.5 mg, yield 33% ). LCMS: 477.2 [M+H] ⁺ , ESI pos.

step C : 5- chlorine -2-[2-[[(3 S ,4 R )-1- Ethyl -4- fluorine -3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-3- methyl - phenol

The above enantiomer 5-chloro-2-[2-[[(3S,4R)-1-ethyl-4-fluoro-3-piperidinyl]amino]oxazolo[4,5-b ]pyridin-5-yl]-3-methyl-phenol (53.4 mg, 104 µmol, 1.0 eq) in DCM (1 mL) and MeOH (0.5 mL) and 4 M HCl in dioxane (310 mg, 260 µL, 1.04 mmol, 10 eq) reaction. The reaction mixture was stirred at room temperature for 3 hours to give 5-chloro-2-[2-[[( 3S , 4R )-4-fluoro-3-piperidinyl]amino]oxazole as light yellow powder a[4,5-b]pyridin-5-yl]-3-methyl-phenol; hydrochloride (50.9 mg, 109%). LCMS: m/z 377.2 [M+H] ⁺ , ESI pos. The mixture was used without further purification in the next step using acetaldehyde according to GP4 . The title compound was obtained as an off-white powder (38.4 mg, 84% yield). LCMS: 405.3 [M+H] ⁺ , ESI pos. Example 99b : 5- Chloro -2-[2-[[(3 R ,4 S )-1- ethyl -4- fluoro -3- piperidinyl ] amino ] oxazolo [4,5-b] Pyridin -5- yl ]-3- methyl - phenol

The above enantiomer 5-chloro-2-[2-[[(3R,4S)-1-ethyl-4-fluoro-3-piperidinyl]amino]oxazolo[4,5-b ]pyridin-5-yl]-3-methyl-phenol (48.5 mg, 102 µmol, 1.0 eq) in DCM (1 mL) and MeOH (0.5 mL) and 4 M HCl in dioxane (254 µL, 1.02 mmol, 10 eq) reaction. The reaction mixture was stirred at room temperature for 3 hours to give 5-chloro-2-[2-[[( 3R , 4S )-4-fluoro-3-piperidinyl]amino]oxazole as a pale yellow powder a[4,5-b]pyridin-5-yl]-3-methyl-phenol; hydrochloride (49.6 mg, 116%). LCMS: m/z 377.2 [M+H] ⁺ , ESI pos. The mixture was used without further purification in the next step using acetaldehyde following the procedure outlined in GP4 . The title compound (32.8 mg, yield 70%) was obtained as light yellow powder. LCMS: m/z 405.3 [M+H] ⁺ , ESI pos. Example 100 : ( 3S , 5R )-5-[[5-[4- chloro -2- hydroxy -6-( methoxymethyl ) phenyl ] oxazolo [4,5-b ] pyridine- 2- yl ] amino ]-1- methyl - piperidin -3- ol

step A : 5- chlorine -3- hydroxyl -2- iodine - Benzaldehyde

To a mixture of 3-chloro-5-hydroxybenzaldehyde (CAS# 1829-33-0, 10.0 g, 63.9 mmol, 1.0 eq) in DMF (100 mL) was added portionwise NaH ( 3.07 g, 127.7 mmol, 2.0 eq, 60%), stirred for 30 minutes, then added iodine (16.2 g, 63.9 mmol, 1.0 eq) in portions, and stirred at 25°C for 15.5 hours. The mixture was poured into a molar aqueous hydrochloric acid solution (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 5:1), and purified by column chromatography (C ₁₈ , 0.1% NH ₃ in water/MeCN). H ₂ O) was purified again to give the title compound (730 mg, 4% yield) as a light green solid. LCMS: m/z 280.9 [MH]-, ESI neg.

step B : 5- chlorine -2- iodine -3-(2- Trimethylsilylethoxymethoxy ) Benzaldehyde

A mixture of Cs ₂ CO ₃ (1263.1 mg, 3.88 mmol, 1.5 eq) and 5-chloro-3-hydroxy-2-iodo-benzaldehyde (730.0 mg, 2.58 mmol, 1.0 eq) in DMF (10 mL) was decomposed gas, blow with N2 three times, and stir for another 30 minutes. Then, a batch of SEM-Cl (646.32 mg, 3.88 mmol, 1.5 eq) was added to the mixture. The mixture was stirred at 25 °C for 2 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (40 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 10:1) to obtain the title compound (700.0 mg, 1.7 mmol, yield 66%) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.02 (s, 1H), 7.48 (d, 1H), 7.38 (d, 1H), 5.46 (s, 2H), 3.76 (t, 2H ), 0.89 (t, 2H), -0.04 (s, 9H).

step C : [5- chlorine -2- iodine -3-(2- Trimethylsilylethoxymethoxy ) Phenyl ] Methanol

Sodium borohydride (77.0 mg, 2.04 mmol, 1.20 eq) was added in small portions to 5-chloro-2-iodo-3-(2-trimethylsilylethoxymethoxy)benzaldehyde (700.0 mg, 1.7 mmol, 1.0 eq) in methanol (7 mL) and water (0.7 mL). The mixture was stirred at 25°C for 3 hours. The mixture was poured into water (15 ml), and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (700.0 mg, 99% yield) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.13 (s, 1H), 7.09 (d, 1H), 5.60 (t, 1H), 5.36 (s, 2H), 4.42 - 4.37 (m , 2H), 3.73 (t, 2H), 0.92 - 0.85 (m, 2H), -0.02-0.05 (m, 9H).

step D. : 2-[[5- chlorine -2- iodine -3-( Methoxymethyl ) Phenoxy ] Methoxy ] Ethyl - Trimethyl - Silane

[5-Chloro-2-iodo-3-(2-trimethylsilylethoxymethoxy)phenyl]methanol (700.0 mg, 1.69 mmol, 1.0 eq) and To a mixture of NaH (97.22 mg, 4.05 mmol, 2.4 eq 60%) in THF (8 mL) was added a portion of Me-I (0.21 mL, 3.38 mmol, 2.0 eq) and stirred for 5 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=0/1 to 5/1), and concentrated under reduced pressure to give the title compound (600.0 mg, yield 83 %). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.12 (d, 1H), 7.07 (d, 1H), 5.37 (s, 2H), 4.38 (s, 2H), 3.78 - 3.70 (m , 2H), 3.38 (s, 3H), 0.91 - 0.85 (m, 2H), -0.03-0.06 (m, 9H).

step E. : 2-[[5- chlorine -2- iodine -3-( Methoxymethyl ) Phenoxy ] Methoxy ] Ethyl - Trimethyl - Silane

2-[[5-Chloro-2-iodo-3-(methoxymethyl)phenoxy]methoxy]ethyl-trimethyl-silane (60.0 mg, 0.14 mmol, 1.0 eq) and bis A mixture of (pinacola) diboron (355.35 mg, 1.4 mmol, 10.0 eq) in 1,4-dioxane (150 mL) was degassed and purged with N2 three times, and a batch of KOAc (68.67 mg , 0.7 mmol, 5.0 eq), Pd(dppf)Cl ₂ (10.24 mg, 0.01 mmol, 0.1 eq) were added to the mixture. The mixture was stirred at 90 °C for 2 hours under microwave irradiation. The mixture was purified by C18 column chromatography (20 g, 0.1% TFA in water/MeCN) to afford the title compound (20.0 mg, 0.05 mmol, 33% yield) as a dark brown oil. ¹ H NMR (400 MHz, CD ₃ OD) δ [ppm]: 7.02 (d, 1H), 6.92 (d, 1H), 5.21 (s, 2H), 4.43 (s, 2H), 3.77 (t, 2H) , 3.29 (s, 3H), 1.37 (s, 12H), 0.96 - 0.90 (m, 3H), 0.005 (s, 9H).

step f : (3 R ,5 S )-3-((5- bromozolo [4,5-b] pyridine -2- base ) Amino )-5- hydroxyl - piperidine -1- Tertiary butyl formate

(3R,5S)-3-Amino-5-hydroxy-piperidine-1-carboxylic acid tertiary butyl ester (CAS # 1932513-59-1, 277.94 mg, 1.29 mmol, 2.5 eq) and DIEA (331.6 mg, 2.57 mmol, 5.0 eq) to a solution in NMP (1 mL) was added 5-bromo-2-chloro-oxazolo[4,5-b]pyridine (120.0 mg, 0.51 mmol, 1.0 eq), at 25°C Stir for 2 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product, which was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to give the title compound (200 mg, yield rate of 94%). ¹ H NMR (400 MHz, CD ₃ OD) δ [ppm]: 7.43 (d, 1H), 7.09 (d, 1H), 3.93 - 3.83 (m, 0.3H), 3.82 - 3.77 (m, 1H), 3.76 -7.75 (m, 0.6H), 3.72 - 3.55 (m, 2H), 3.41 - 3.29 (m, 0.5H), 3.18 - 3.06 (m, 0.5H), 3.04-2.87 (m, 1H), .2.5- 2.17 (m, 1H), 1.67 - 1.50 (m, 1H), 1.37 - 1.15 (m, 9H).

step G : (3 S ,5 R )-5-[(5- bromozolo [4,5-b] pyridine -2- base ) Amino ] piperidine -3- alcohol; hydrochloride

(3 R ,5 S )-3-[(5-Bromozozolo[4,5-b]pyridin-2-yl)amino]-5-hydroxy-piperidine-1-carboxylic acid tertiary butyl ester (200.0 mg, 0.48 mmol, 1.0 eq) and HCl/dioxane (2.0 mL, 8.0 mmol, 16.53 eq) were stirred at 25°C for 2 hours. The mixture was concentrated in vacuo to give the crude product, which was purified by reverse phase flash chromatography (water (0.1% HCl)-MeCN) to give the title compound (160 mg, 95% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ [ppm]: 7.59 (d, 1H), 7.25 (d, 1H), 4.30 - 4.21 (m, 1H), 4.16-4.11 (m, 1H), 3.53- 3.38 (m, 1H), 3.38-3.37 (m, 0.5H), 3.33-3.32 (m, 0.5H), 3.26-3.23 (m, 1H), 3.06-3.01(m, 1H), 2.35-2.30 (m , 1H), 1.97-1.90 (m, 1H).

step h : (3 S ,5 R )-5-[(5- bromozolo [4,5-b] pyridine -2- base ) Amino ]-1- methyl - piperidine -3- alcohol; 2,2,2- Trifluoroacetate

Under N2, to (3 S ,5 R )-5-[(5-bromozozolo[4,5-b]pyridin-2-yl)amino]piperidin-3-ol; hydrochloride ( 150.0 mg, 0.43 mmol, 1.0 eq), NaOAc (42.23 mg, 0.51 mmol, 1.2 eq) in methanol (2 mL) was added formaldehyde (104.45 mg, 1.29 mmol, 3.0 eq, 37%), and at 25 Stir for 0.5 h at °C, then add _NaBH3CN (134.81 mg, 2.15 mmol, 5.0 eq) and continue stirring at 25 °C for 1.5 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to afford the title compound (130.0 mg, 67% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ [ppm]: 7.58 (d, 1H), 7.24 (d, 1H), 4.47 - 4.13 (m, 2H), 3.57 - 3.31 (m, 4H), 2.94 ( s, 3H), 2.43 - 2.00 (m, 2H).

step I : (3 S ,5 R )-5-[[5-[4- chlorine -2-( Methoxymethyl )-6-(2- Trimethylsilylethoxymethoxy )- Phenyl ] zozolo [4,5-b] pyridine -2- base ] Amino ]-1- methyl - piperidine -3- alcohol

K ₂ CO ₃ (16.92 mg, 0.12 mmol, 2.5 eq), 2-[[5-chloro-3-(methoxymethyl)-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy]methoxy]ethyl-trimethyl-silane (21.0 mg, 0.05 mmol, 1.0 eq) and (3 S ,5 R )-5-[(5-Bromozozolo[4,5-b]pyridin-2-yl)amino]-1-methyl-piperidin-3-ol; 2,2,2-trifluoroacetic acid (28.1 mg, 0.06 mmol, 1.3 eq) in 1,4-dioxane (1 mL) and water (0.200 mL) was degassed, and purged with N2 three times, then XPhos Pd G3 (4.12 mg, 0.0 mmol, 0.1 eq) was added to the mixture. The mixture was heated at 95°C for 2 hours under microwave irradiation. The mixture was concentrated under reduced pressure and purified by C18 column chromatography (20 g, 0.1% NH ₃ ·H ₂ O in water/MeCN) to give the title compound as a red oil (20.0 mg, yielding rate of 74%). ¹ H NMR (400 MHz, CD ₃ OD) δ [ppm]: 7.80 (d, 1H), 7.24 (d, 1H), 7.21 (s, 1H), 7.08 (d, 1H), 5.13 (s, 2H) , 4.76 - 4.58 (m, 1H), 4.49 - 4.32 (m, 1H), 4.21 (s, 2H), 3.95 - 3.75 (m, 1H), 3.59 (t, 2H), 3.53 - 3.37 (m, 1H) , 3.26 ( s, 1H), 3.21 (s, 3H), 2.94 (s, 3H), 2.89 - 2.66 (m, 1H), 2.60 - 2.43 (m, 1H), 2.30 - 2.03 (m, 2H), 1.79 - 1.53 (m, 1H), 0.86 (t, 2H), -0.04 (s, 9H).

step J : (3 S ,5 R )-5-[[5-[4- chlorine -2- hydroxyl -6-( Methoxymethyl ) Phenyl ] zozolo [4,5-b] pyridine -2- base ] Amino ]-1- methyl - piperidine -3- alcohol

(3 S ,5 R )-5-[[5-[4-chloro-2-(methoxymethyl)-6-(2-trimethylsilylethoxymethoxy)phenyl] Zazolo[4,5-b]pyridin-2-yl]amino]-1-methyl-piperidin-3-ol (20.0 mg, 0.04 mmol, 1.0 eq) and TFA (0.5 mL, 6.73 mmol, A solution of 184.82 eq) in DCM (1 mL) was stirred at 25°C for 2 hours. The residue was purified by C18 column chromatography (20 g, 0.1% TFA in water/MeCN) to afford the title compound (8.63 mg, 54% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ [ppm]: 7.90 (d, 1H), 7.20 (d, 1H), 7.04 (d, 1H), 6.92 (d, 1H), 4.80 - 4.34 (m, 2H), 4.24 (s, 2H), 4.06 - 3.79 (m, 1H), 3.69 - 3.36 (m, 2H), 3.21 (s, 3H), 2.95 (s, 3H), 2.85 - 2.66 (m, 1H) , 2.26 - 2.07 (m, 1H), 2.03 (s, 1H), 1.94 - 1.49 (m, 1H). Example 101 : 1-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ]-5-[2- hydroxyl -6- methyl -4-( trifluoromethyl ) Phenyl ] -oxazolo [4,5-b] pyridin -7- yl ] tetrahydroacrin -3- ol

step A : 2-[7- chlorine -2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

(3 R )-3-[[7-chloro-5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine -2-yl]amino]piperidine-1-carboxylic acid tert- butyl ester (275.0 mg, 0.46 mmol, 1.0 eq) was dissolved in DCM (15 mL), and boron tribromide (1 M in DCM) was added ( 2.29 mL, 2.29 mmol, 5.0 eq). The mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The resulting residue was dissolved in 0.7 N ammonia in MeOH (5 mL), then concentrated in vacuo. The resulting residue was dissolved in EtOH (10 mL), and one drop of AcOH was added, followed by acetaldehyde (0.1 mL, 1.83 mmol, 4.0 eq). The reaction was stirred for 1 hour, then STAB (242.42 mg, 1.14 mmol, 2.5 eq) was added. The reaction was stirred for 1 h, then wet MeOH (5 mL) and the mixture were stirred at room temperature for 45 min. The reaction mixture was dry loaded onto silica and purified by silica gel flash chromatography (12 g column, 0% to 10% (0.7 N ammonia in MeOH/DCM)) to give the title compound as a light brown solid (195 mg, 93% yield). LCMS m/z 455.2 [M+H] ⁺ , ESI pos.

step B : 1-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ]-5-[2- hydroxyl -6- methyl -4-( Trifluoromethyl )- Phenyl ] zozolo [4,5-b] pyridine -7- base ] Tetrahydroacridine -3- alcohol

2-[7-Chloro-2-[[(3 R )-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Methyl-5-(trifluoromethyl)phenol ( Example 101 , Step A ) (150 mg, 0.33 mmol, 1.0 eq) was dissolved in NMP (2 mL) and 3-hydroxytetrahydroacridine (482.1 mg , 6.6 mmol, 20.0 eq). The mixture was sealed in a tube and stirred at 80°C for 24 hours. The reaction mixture was diluted to 5.1 mL with DMSO, filtered, and supplemented by reverse phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organizer, Waters 515 ACD Pump, Waters 515 pump, Waters 2998 photodiode array detector, Waters QDa) were purified on a Waters XBridge BEH C ₁₈ ODB preparative column (130 Å, 5 µm, 30 mm × 100 mm) (flow rate 40 mL·min ^-1 , eluted with a gradient of 0.3% ammonia in water-MeCN over 12.5 min, UV at all wavelengths obtained using PDA and QDA and ELS detectors). Throughout the method, the on-column dilution pump delivered 2 mL·min ⁻¹ methanol, which is contained in the following MeCN percentages. Gradient profile: 0.0 min to 0.5 min at 25% MeCN; 0.5 min to 10.5 min in increments from 25% MeCN to 55% MeCN; 10.5 min to 10.6 min in increments from 55% MeCN to 100% MeCN; 10.6 min to 12.5 min , kept at 100% MeCN. The title compound was thus obtained as a white solid (6.35 mg, yield 3.7%). LCMS m/z 492.3 [M+H] ⁺ , ESI pos. Example 102 : 1-[5-[2- Hydroxy -6- methyl -4-( trifluoromethyl ) phenyl ]-2-[[(3 R )-1- methyl -3- piperidinyl ] Amino ] oxazolo [4,5-b] pyridin -7- yl ] ethanone; 2,2,2- trifluoroacetic acid

step A : 6- chlorine -4- iodine -2- Nitropyridine -3- alcohol

The device was dried by heating with an air heater under vacuum. In a three-neck round-bottom flask, dissolve 6-chloro-4-iodo-pyridin-3-ol (CAS: 877133-58-9; 5.0 g, 19.57 mmol, 1.0 eq) in acetic acid (50 mL) at 20°C Fuming nitric acid (2.45 mL, 58.72 mmol, 3.0 eq) was added, and the mixture was stirred at 20°C for 2 hours. The reaction mixture was cooled to room temperature. Pipette it slowly into 100 mL of saturated aqueous _NaHCO3 . Gas evolution was observed. EtOAc (120 mL) and water (120 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (100 mL x 2). The combined extracts were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give a yellow solid. The solid was purified by column (PE:EA = 4:1 to 2:1) to give the title compound (2.7 g, 46% yield) as a yellow solid. LCMS: m/z 301.0 [M+H] ⁺ , ESI pos.

step B : 2- Amino -6- chlorine -4- Iodopyridine -3- alcohol

To the above mixture of 6-chloro-4-iodo-2-nitro-pyridin-3-ol (2.8 g, 9.32 mmol, 1.0 eq) in methanol (28 mL) was added tin(ll) chloride (8.84 g , 46.6 mmol, 5.0 eq), and the mixture was stirred at 70°C for 2 hours. The reaction mixture was cooled to room temperature. EtOAc (80 mL) and water (80 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (60 mL x 2). The combined extracts were washed with brine (80 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give a yellow solid. The residue was purified by column (PE:EA = 5:1 to 1:1) to give the title compound (1.7 g, 67% yield) as a yellow solid. LCMS: m/z 270.9 [M+H]+, ESI pos.

step C : 5- chlorine -7- Iodozozolo [4,5-b] pyridine -2- Thiol

The device was dried by heating with an air heater under vacuum. To a mixture of 2-amino-6-chloro-4-iodo-pyridin-3-ol (2.3 g, 8.5 mmol, 1.0 eq) in THF (23 mL) was added TCDI (3.03 g, 17.01 mmol, 2.0 eq ), and the mixture was stirred at 50°C for 12 hours. The reaction mixture was cooled to room temperature. EtOAc (30 mL) and water (40 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (40 mL x 2). The combined extracts were washed with brine (40 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give a brown oil. The residue was purified by column (PE:EA = 10:1 to 5:1) to give the title compound (1.3 g, 49% yield) as a brown oil. LCMS: m/z 313.0 [M+H] ⁺ , ESI pos.

step D. : 2,5- Dichloro -7- Iodozozolo [4,5-b] pyridine

To 5-chloro-7-iodo-7,7a-dihydrooxazolo[4,5-b]pyridine-2-thiol (900 mg, 2.86 mmol, 1.0 eq) in oxalyl chloride (12.1 mL, 143.07 mmol, 50.0 eq) was added DMF (20.9 mg, 0.29 mmol, 0.1 eq), and the mixture was stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature. EtOAc (20 mL) and water (20 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (20 mL x 2). The combined extracts were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give a yellow solid. The solid was purified by column (PE:EA = 5:1 to 2:1) to give the title compound (360.0 mg, 1.14 mmol, 40% yield) as a yellow solid. LCMS: m/z 314.9 [M+H] ⁺ , ESI pos.

step E. : ( R )-5- chlorine -7- iodine -N-(1- Methylpiperidine -3- base ) zozolo [4,5-b] pyridine -2- amine 2,2,2- Trifluoroacetate

To a mixture of ( 3R )-1-methylpiperidin-3-amine (377.1 mg, 3.3 mmol, 2.0 eq) in MeCN (5 mL) was added 2,5-dichloro-7-iodo-oxazole Do[4,5-b]pyridine (520.0 mg, 1.65 mmol, 1.0 eq) and DIEA (0.54 mL, 3.3 mmol, 2.0 eq), then the mixture was stirred at 25°C for 0.5 hours. The reaction mixture was quenched by adding 1 ml of water, then diluted with 3 ml of MeOH to give a brown mixture. The mixture was purified by reverse phase flash chromatography (0.1% TFA water/ACN conditions). The eluate was dried by lyophilization to obtain a yellow solid. The solid was subjected to preparative HPLC (column: 3_Phenomenex Luna C18 75 × 30 mm × 3 um; condition: water (TFA)-ACN; B at the beginning: 15; B at the end: 35; gradient time (minutes): 9; 100% B hold time (min): 2; flow rate (ml/min): 25) was purified again to give the title compound (325 mg, 50% yield) as a yellow solid. LCMS: m/z 393.1 [M+H] ⁺ , ESI pos.

step f : ( R )-1-(5- chlorine -2-((1- Methylpiperidine -3- base ) Amino ) zozolo [4,5-b] pyridine -7- base ) Second -1- ketone

5-Chloro-7-iodo- N -[(3 R )-1-methyl-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine (100.0 mg, 0.25 mmol, 1.0 eq) and tributyl(1-ethoxyvinyl)stannane (0.44 g, 1.21 mmol, 4.77 eq) in DMF (3 mL) were degassed with nitrogen for 5 minutes. Pd(PPh ₃ ) ₄ (58.78 mg, 0.05 mmol, 0.2 eq) was added, and the mixture was heated to 80° C. for 6 hours. The reaction mixture was cooled to room temperature. EtOAc (20 mL) and water (20 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (30 mL x 2). The combined extracts were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give a white solid. The residue was purified by column (PE:EA = 20:1 to 10:1) to give the title compound (40.0 mg, yield 51%) as a white solid . LCMS: m/z 309.2 [M+H]+, ESI pos.

step G : 1-[5-[2- hydroxyl -6- methyl -4-( Trifluoromethyl ) Phenyl ]-2-[[(3R)-1- methyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -7- base ] ethyl ketone ; 2,2,2- Trifluoroacetate

Under nitrogen gas, to 1-[5-chloro-2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-7-yl ] Ethanone (10.0 mg, 0.03 mmol, 1.0 eq) and [2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl] boronic acid (28.49 mg, 0.13 mmol, 4.0 eq) in 1,4 - To a solution in dioxane (1 mL) and water (0.2 mL) was added CsF (19.7 mg, 0.13 mmol, 4.0 eq) and XPhos Pd G3 (2.74 mg, 0.0 mmol, 0.1 eq). The mixture was stirred at 95 °C for 5 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by C18 column chromatography (20 g, 0.1% TFA in water/MeCN) to afford the title compound (5.03 mg, 34% yield) as a white solid. LCMS: m/z 449.2 [M+H]+, ESI pos. Example 103 : 2-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ]-7-( methylamino ) oxazolo [4,5-b ] pyridine- 5- yl ]-3- methyl -5-( trifluoromethyl ) phenol

step A : (3 R )-3-[[5-[2- Methoxy -6- methyl -4-( Trifluoromethyl ) Phenyl ] zozolo [4,5-b] pyridine -2- base ] Amino ] piperidine -1- Tertiary butyl formate

2-[2-Methoxy-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxolane Borane (725.71 mg, 2.3 mmol, 1.2 eq), XPhos Pd G3 (121.59 mg, 0.14 mmol, 0.08 eq), saturated aqueous NaHCO ₃ (1.75 mL) and tertiary -butyl-(3 R )-3-[ (5-Bromozozolo[4,5-b]pyridin-2-yl)amino]piperidine-1-carboxylate ( Example 75 , Step A ) (760 mg, 1.91 mmol, 1.0 eq) was suspended in 1,4-Dioxane (12 mL) and degas with N ₂ (5 min). The reaction mixture was heated to 80 °C and stirred for 90 minutes. The reaction mixture was cooled, dry loaded onto silica gel, and purified by chromatography (silica gel, 0% to 10% MeOH/DCM) to afford the title compound (824 mg, 71% yield) as a yellow solid. LCMS m/z 541.4 ( ³⁵ Cl) [M+H]+, ESI pos.

step B : (3 R )-3-[[5-[2- Methoxy -6- methyl -4-( Trifluoromethyl ) Phenyl ]-4- Oxygen group - zozolo [4,5-b] pyridine -4- Onium -2- base ] Amino ] piperidine -1- Tertiary butyl formate

Add methyl trioxyrhenium (vii) (79.7 mg, 0.32 mmol, 0.2 eq) to 30% aqueous hydrogen peroxide (0.82 mL, 8.0 mmol, 5.0 eq) and (3R)-3-[[5-[ 2-Methoxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amino]piperidine-1-carboxylic acid tertiary butyl In a stirred solution of the ester (900.0 mg, 1.6 mmol, 1.0 eq) in MeOH (12 mL). The reaction mixture was stirred at room temperature for 2 hours, then additional methyl trioxorhenium(vii) (83.7 mg, 0.34 mmol, 0.2 eq) was added and stirred at room temperature for 24 hours. The reaction mixture _was added slowly to stirred 10 wt% aqueous _Na2SO3 (30 mL) at 0 °C. The mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried using a phase separator and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel, 0% to 10% MeOH/DCM) to afford the title compound (600 mg, 62%) as a pale yellow solid. LCMS m/z 523.4 [M+H] ⁺ , ESI pos.

step C : (3 R )-3-[[7- chlorine -5-[2- Methoxy -6- methyl -4-( Trifluoromethyl )- Phenyl ] zozolo [4,5-b] pyridine -2- base ] Amino ] piperidine -1- Tertiary butyl formate

(3 R )-3-[[5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-4-oxanionyl-oxazolo[4,5- b] Pyridin-4-ium-2-yl]amino]piperidine-1- carboxylic acid tert-butyl ester ( Example 103 , Step B ) (420 mg, 0.8 mmol, 1.0 eq) was dissolved in DMF (12 mL) , and oxalyl chloride (0.41 mL, 4.82 mmol, 6.0 eq) was added slowly under vigorous stirring at 0 °C. The mixture was stirred at room temperature for 2 h, then 2 N aqueous NaOH (2 mL) was added, and the mixture was further stirred for 45 min. The mixture was diluted with EtOAc (30 mL), washed with 10 wt% aqueous LiCl (3 x 25 mL), dried using a phase separator, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (12 g column, 0% to 10% MeOH/DCM) to afford the title compound (300 mg, 62% yield) as a light brown gum. LCMS m/z 541.4 ( ³⁵ Cl) [M+H]+, ESI pos.

step D. : (3 R )-3-[[7-[ Level three - Butoxycarbonyl ( methyl ) Amino ]-5-[2- Methoxy -6- methyl -4-( Trifluoromethyl ) Phenyl ] zozolo [4,5-b] pyridine -2- base ] Amino ] piperidine -1- Tertiary butyl formate

Tri -butyl N -methylcarbamate (270.6 mg, 2.06 mmol, 10.0 eq), XPhos Pd G3 (52.39 mg, 0.06 mmol, 0.3 eq), XPhos (29.5 mg, 0.06 mmol, 0.3 eq), (3 R )-3-[[7-chloro-5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine-2- Base]amino]piperidine-1-carboxylic acid tertiary butyl ester (120.0 mg, 0.21 mmol, 1.0 eq) and Cs ₂ CO ₃ (336.1 mg, 1.03 mmol, 5.0 eq) were suspended in 1,4-dioxane ( 2 mL), and the mixture was degassed (N ₂ , 5 min). The mixture was stirred at 80°C for 4 hours. The mixture was cooled and additional XPhos (29.5 mg, 0.06 mmol, 0.3 eq) and XPhosPdG3 (52.39 mg, 0.06 mmol, 0.3 eq) were added. The mixture was placed under nitrogen and further stirred at 80 °C for 16 hours. The reaction mixture was cooled, diluted with water (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried using a phase separator and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel, 0% to 10% MeOH/DCM) to afford the title compound (76.0 mg, 32%) as a yellow oil. LCMS m/z 636.5 [M+H]+, ESI pos.

step E. : 2-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ]-7-( Methylamino ) zozolo [4,5-b] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

(3 R )-3-[[7-[tertiary-butoxycarbonyl (methyl)amino]-5-[2-methoxy-6-methyl-4-(trifluoro-methyl )phenyl]oxazolo[4,5-b]pyridin-2-yl]amino]piperidine-1-carboxylic acid tert -butyl ester (76.0 mg, 0.07 mmol, 1.0 eq) was dissolved in DCM (4 mL) , and added boron tribromide (1 M in DCM) (0.33 mL, 0.33 mmol, 5.0 eq). The mixture was stirred at room temperature for 16 hours, then concentrated in vacuo . The resulting residue was dissolved in 0.7 N ammonia in MeOH (5 mL), then concentrated in vacuo. The resulting residue was dissolved in EtOH (4 mL), and one drop of AcOH was added, followed by acetaldehyde (0.02 mL, 0.27 mmol, 4.0 eq). The reaction was stirred for 1 hour, then STAB (56.76 mg, 0.27 mmol, 4.0 eq) was added. The reaction was stirred for 1 h, then wet MeOH (5 mL) was added, and the mixture was stirred for 30 min. The reaction mixture was dry loaded onto silica and purified by silica gel flash chromatography (4 g column, 0% to 20% (0.7 N ammonia in MeOH)/DCM) to afford the title compound ( 17.4 mg, yield 50%). LCMS: m/z 450.4 [M+H]+, ESI pos. Example 104 : 2-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ]-7- methoxy - oxazolo [4,5-b] pyridine -5- Base ] -3- methyl -5-( trifluoromethyl ) phenol

step A : 6- bromine -4- Methoxy -2- nitro - pyridine -3- alcohol

To a magnetically stirred solution of 4,6-dibromo-2-nitro-pyridin-3-ol (450 mg, 1.5 mmol, 1.0 eq) in DMSO (12 mL) was added sodium methylthiolate (81.6 mg, 1.51 mmol, 1.00 eq). The reaction mixture was heated at 60 °C for 30 minutes, then additional sodium methylthiolate (1.5 eq) was added and stirring was continued for 6 hours. The reaction mixture was cooled to 15°C to 20°C and quenched with 1.5 N HCl. The aqueous layer (pH ca. 1) was extracted twice with MTBE. The combined organic layers were concentrated and the crude product was purified by normal phase chromatography (DCN-MeOH 0% to 10%) to afford the title compound (239 mg, 60% yield) as a yellow solid. LCMS m/z: 251 [M+H] ⁺ , ESI pos.

step B : 6-[2- hydroxyl -6- methyl -4-( Trifluoromethyl ) Phenyl ]-4- Methoxy -2- nitro - pyridine -3- alcohol

6-Bromo-4-methoxy-2-nitro-pyridin-3-ol (55 mg, 210 µmol, 1.0 eq), 3-methyl-2-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (100 mg, 315 µmol, 1.5 eq), cesium carbonate (136.7 mg, 420 µmol, 2.0 eq) and XPhos Pd G3 (18.7 mg, 22.0 µmol, 0.105 eq) in 1,4-dioxane (1 mL) and water (0.25 mL) were flushed with argon and stirred at 90°C overnight. The mixture was cooled to ambient temperature, filtered through celite, and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (column: YMC-Triart C ₁₈ , 12 nm, 5 µm, 100×30 mm; gradient: MeCN/water+0.1% HCOOH) to give the title compound (17 mg, yield rate 23%). ¹ H NMR (300 MHz, CDCl ₃ ) δ [ppm]: 2.54 (s, 3 H) 4.08 (s, 3 H) 7.10 (s, 1 H) 7.16 - 7.19 (m, 1 H) 7.33 (s, 1 H) 10.10 (s, 1 H) 10.31 - 10.52 (m, 1 H). The reaction was repeated on a larger scale.

step C : 2- Amino -6-[2- hydroxyl -6- methyl -4-( Trifluoromethyl ) Phenyl ]-4- Methoxy - pyridine -3- alcohol

6-[2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methoxy-2-nitro-pyridin-3-ol (122 mg, 354 µmol, 1.0 eq ) was dissolved in methanol (12.2 mL), and Pd/C (12.2 mg, 11.46 µmol, 0.032 eq) was added at room temperature. The mixture was degassed 3 times, then stirred under _H2 for 1 h. The reaction mixture was filtered through celite, rinsed with MeOH, and evaporated to dryness to give the title compound (104.9 mg, 91%) as a dark green powder. The product was used directly in the next step without any further purification. LCMS m/z: 315.2 [M+H] ⁺ , ESI pos.

step E. : 2-[7- Methoxy -2-( Methylthio ) zozolo [4,5- b ] pyridine -5- base ]-3- methyl -5-( Trifluoro - methyl ) phenol

2-Amino-6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-4-methoxy-pyridin-3-ol (104 mg, 331 µmol, 1.0 eq) in DMF (1.1 mL) was added 1,1'-thiocarbonyldiimidazole (59 mg, 331 µmol, 1.0 eq). The reaction mixture was stirred overnight at room temperature. Then, K ₂ CO ₃ (91.5 mg, 662 µmol, 2.0 eq) and iodomethane (54.5 mg, 24 µL, 384 µmol, 1.16 eq) were added sequentially. The reaction mixture was stirred at room temperature for 30 minutes. After cooling to room temperature, the mixture was extracted with ammonium chloride, water and ethyl acetate. The aqueous layer was back extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Gradient: 0% to 20% ethyl acetate in heptane) to afford the title compound (98.5 mg, 79% yield) as a white foam. LCMS m/z: 371.1 [M+H] ⁺ , ESI pos.

step f : 2-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ]-7- Methoxy - zozolo [4,5-b] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

Under stirring, 2-[7-methoxy-2-(methylthio)oxazolo[4,5- b ]pyridin-5-yl]-3-methyl-5-(trifluoromethyl )phenol (32.6 mg, 86 µmol, 1.0 eq) to a colorless mixture in 1,4-dioxane (400 µL) was successively added [(3 R )-1-ethyl-3-piperidinyl at room temperature ]amine (13.0 mg, 102 µmol, 1.18 eq) and triethylamine (10.1 mg, 13.9 µL, 100 µmol, 1.16 eq). The solution was stirred at 90 °C for 3 days. Then, NEt ₃ (10.1 mg, 13.9 µL, 100 µmol, 1.16 eq) and [(3 R )-keto-ethyl-3-piperidinyl]amine (13 mg, 102 µmol, 1.18 eq) were added, and Stirring was continued overnight at 90°C. After cooling to room temperature, the mixture was extracted with EtOAc, water and ammonium chloride. The aqueous layer was back extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was subjected to preparative HPLC (column: Gemini NX, 12 nm, 5 µm, 100 × 30 mm; gradient: MeCN/water + 0.1% TEA) to give the title compound (13.1 mg, yield 30%). LCMS m/z: 451.2 [M+H] ⁺ , ESI pos. Examples 105 and 106 : 2-[7-(1- Hydroxy -1- methyl - ethyl )-2-[[( 3R )-1- methyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridin -5- yl ]-3- methyl -5-( trifluoromethyl ) phenol; 2,2,2- trifluoroacetic acid and 2-[7-(1- hydroxyethyl )-2-[[(3 R )-1- methyl - 3- piperidinyl ] amino ] oxazolo [4,5-b] pyridin -5- yl ]-3- methyl -5-( Trifluoromethyl ) phenol

step A : ( R )-5- chlorine -2-((1- Methylpiperidine -3- base ) Amino ) zozolo [4,5-b] pyridine -7- Methyl formate

To ( R )-5-chloro-7-iodo- N- (1-methylpiperidin-3-yl)oxazolo[4,5-b]pyridin-2-amine ( Example 60 , step E ) ( To a solution of 90.0 mg, 0.23 mmol, 1.0 eq) and methanol (172.1 mg, 3.44 mmol, 15.0 eq) in DMF (5 mL) was added TEA (116 mg, 1.15 mmol, 5.0 eq) and Pd(dppf)Cl ₂ (16.8 mg, 0.02 mmol, 0.1 eq). The mixture was degassed three times with nitrogen and stirred at 80 °C for 3 h under 2280 mmHg of CO gas. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (C ₁₈ , 0.1% TFA in water-MeCN) to afford the title compound (60.0 mg, 81% yield) as a yellow solid. LCMS: m/z 325.1 [M+H] ⁺ , ESI pos.

step B : ( R )-2-(5- chlorine -2-((1- Methylpiperidine -3- base ) Amino ) zozolo [4,5-b] pyridine -7- base ) C -2- Alcohol and ( R )-1-(5- chlorine -2-((1- Methylpiperidine -3- base ) Amino ) zozolo [4,5-b] pyridine -7- base ) Second -1- ketone

( R )-5-chloro-2-((1-methylpiperidin-3-yl)amino)oxazolo[4,5-b]pyridine-7-carboxylic acid under nitrogen atmosphere at -65°C To a solution of the methyl ester (40.0 mg, 0.12 mmol, 1.0 eq) in THF (5 mL) was added methyllithium (0.88 mL, 1.23 mmol, 10.0 eq) dropwise and stirring was continued for 2 hours. The mixture was quenched with -50°C water (1 mL), and concentrated under reduced pressure. The residue was purified by column chromatography (C ₁₈ , 0.1% TFA in water/MeCN) to afford (R)-2-(5-chloro-2-((1-methylpiperene) as a yellow oil Pyridin-3-yl)amino)oxazolo[4,5-b]pyridin-7-yl)propan-2-ol (20.0 mg, yield 50%) and yellow oily 1-( R )-1 -(5-Chloro-2-((1-methylpiperidin-3-yl)amino)oxazolo[4,5-b]pyridin-7-yl)ethan-1-one (10.0 mg, yield rate 26%). (R)-2-(5-Chloro-2-((1-methylpiperidin-3-yl)amino)oxazolo[4,5-b]pyridin-7-yl)propan-2-ol LCMS: m/z 325.4, [M+H] ⁺ , ESI pos.

step C : 2-[7-(1- hydroxyl -1- methyl - Ethyl )-2-[[(3 R )-1- methyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol; 2,2,2- Trifluoroacetic acid and ( R )-1-(5-(2- hydroxyl -6- methyl -4-( Trifluoromethyl ) Phenyl )-2-((1- Methylpiperidine -3- base ) Amino ) zozolo [4,5-b] pyridine -7- base ) Second -1- ketone

The device was dried by heating with an air heater under vacuum. To ( R )-2-(5-chloro-2-((1-methylpiperidin-3-yl)amino)oxazolo[4,5-b]pyridin-7-yl)propane at 25°C -2-ol (20.0 mg, 0.06 mmol, 1.0 eq), 1-( R )-1-(5-chloro-2-((1-methylpiperidin-3-yl)amino)oxazolo[ 4,5-b]pyridin-7-yl)ethan-1-one (9.5 mg, 0.03 mmol, 0.5 eq), CsF (46.77 mg, 0.31 mmol, 5.0 eq) and [2-hydroxy-6-methyl- 4-(Trifluoromethyl)phenyl]boronic acid (40.63 mg, 0.18 mmol, 3.0 eq) To a mixture in 1,4-dioxane (1 mL)/water (0.2 mL) was added XPhos Pd G3 (5.22 mg, 0.01 mmol, 0.1 eq). The mixture was stirred in the microwave at 125°C for 2 hours. After cooling to ambient temperature, the mixture was quenched by adding water (10 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by C ₁₈ column chromatography (20 g, 0.1% TFA in water/MeCN) to afford (R)-2-(7-(2-hydroxypropan-2- Base)-2-((1-methylpiperidin-3-yl)amino)oxazolo[4,5-b]pyridin-5-yl)-3-methyl-5-(trifluoromethyl ) phenol; 2,2,2-trifluoroacetic acid (16.4 mg, 0.03 mmol, 44% yield). LCMS: m/z 465.2, (M+H) ⁺ (ESI ⁺ ); and ( R )-1-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)) as light yellow solid Phenyl)-2-((1-methylpiperidin-3-yl)-amino)oxazolo[4,5-b]pyridin-7-yl)ethan-1-one (5.0 mg, yield 18%). LCMS: m/z 449.2 [M+H]+, ESI pos.

step D. : 2-[7-(1- Hydroxyethyl )-2-[[(3 R )-1- methyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

To ( R )-1-(5-(2-hydroxyl-6-methyl-4-(trifluoromethyl)phenyl)-2-((1-methylpiperidin-3-yl)amino) To a solution of oxazolo[4,5-b]pyridin-7-yl)ethan-1-one (5.0 mg, 0.01 mmol, 1.0 eq) in methanol (1 mL) was added NaBH ₄ (0.84 mg, 0.02 mmol , 2.0 eq), and the mixture was stirred at 25 °C for 0.5 h. After filtration, the solvent was removed under reduced pressure and the crude product was purified by C ₁₈ column chromatography (20 g, 0.1% NH ₃ ·H ₂ O in water/MeCN) to afford the title compound as a yellow solid (2.31 mg, 43% yield). LCMS: m/z 451.1 [M+H]+, ESI pos. Example 107 : 3- Chloro -4-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridin -5- yl ]- 5- Hydroxy - benzonitrile; 2,2,2- trifluoroacetic acid

step A : 3- chlorine -5- hydroxyl -4- iodobenzoic acid

To a mixture of 3-chloro-5-hydroxybenzoic acid (CAS: _53984-36-4 ; 0.205 g, 1.19 mmol, 1.0 eq) in DMF (10 mL) was added NaH (172.0 mg, 4.3 mmol, 3.62 eq), stirred for 30 minutes, then added a solution of I ₂ (238.0 mg, 0.94 mmol, 0.79 eq) in DMF (2 mL) at 20°C and stirred at 25°C for 15.5 hours. The reaction mixture was cooled to room temperature, EtOAc (30 mL) and water (30 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (30 mL x 2). The combined extracts were washed with brine (40 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether/EtOAc = 1:1) to give the title compound (70.0 mg, yield 20%) as a yellow oil. LCMS: m/z 296.8 [MH]-, ESI neg.

step B : 3- chlorine -5- hydroxyl -4- methyl iodobenzoate

To a solution of 3-chloro-5-hydroxy-4-iodo-benzoic acid (3.5 g, 11.73 mmol, 1.0 eq) in methanol (35 mL) was added sulfuric acid (664.99 mg, 6.64 mmol, 0.57 eq). The mixture was stirred at 80 °C for 6 hours. The reaction mixture was cooled to room temperature, EtOAc (60 mL) and water (60 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (70 mL x 2). The combined extracts were washed with brine (80 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude product was purified by column (PE:EA = 5:1 to 1:1) to give the title compound (3.30 g, 90% yield) as a yellow solid. LCMS: m/z 310.9 [MH] ^- , ESI neg.

step C : 3- chlorine -5- hydroxyl -4- iodobenzamide

TBD ( ₄₄₄ mg, 3.19 mmol, 0.3 eq). The mixture was stirred at 50°C for 12 hours in a sealed tube. The reaction mixture was cooled to room temperature, EtOAc (60 mL) and water (60 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (60 mL x 2). The combined extracts were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow solid. The solid was purified by column (PE:EA = 5:1 to 1:1) to give the title compound (820.0 mg, 2.76 mmol, 26% yield) as a yellow solid. LCMS: m/z 297.9 [MH] ^- , ESI neg.

step D. : 3- chlorine -5- hydroxyl -4- Iodobenzonitrile

To a solution of 3-chloro-5-hydroxy-4-iodo-benzamide (100.0 mg, 0.34 mmol, 1.0 eq) in THF (3 mL) was added _SOCl2 (0.12 mL, 1.68 mmol, 5.0 eq) . The mixture was stirred at 50 °C for 12 hours. The reaction mixture was cooled to room temperature, EtOAc (20 mL) and water (20 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (20 mL x 2). The combined extracts were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The solid was purified by column chromatography (PE:EA = 10:1 to 1:1) to give the title compound (70.0 mg, 75% yield) as a yellow solid. LCMS: m/z 277.9 [MH]-, ESI neg.

step E. : (2- chlorine -4- cyano -6- Hydroxyphenyl ) boric acid

To 3-chloro-5-hydroxy-4-iodo-benzonitrile (70.0 mg, 0.25 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl- To a mixture of 2,2'-bi(1,3,2-dioxaborolane) (253.5 mg, 1.0 mmol, 4.0 eq) in 1,4-dioxane (1 mL) was added KOAc ( 73.8 mg, 0.75 mmol, 3.0 eq) and Pd(dppf)Cl ₂ (18.31 mg, 0.03 mmol, 0.1 eq), and the mixture was stirred at 95°C for 4 hours. The reaction mixture was cooled to room temperature, EtOAc (20 mL) and water (20 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (20 mL x 2). The combined extracts were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The solid was purified by column (PE:EA = 10:1 to 1:1) to give the title compound (40.0 mg, 57% yield) as a white solid.

step f : 3- chlorine -4-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-5- hydroxyl - Benzonitrile; 2,2,2- Trifluoroacetate

To (2-chloro-4-cyano-6-hydroxy-phenyl)boronic acid (40.0 mg, 0.2 mmol, 1.0 eq) and 5-bromo-N-[(3 R )-1-ethane under N ₂ yl-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine; 2,2,2-trifluoroacetic acid ( Example 21 , Step H ) (106.8 mg, 0.24 mmol, 1.2 eq) To a solution in 1,4-dioxane (1 mL) and water (0.2 mL) was added CsF (123.1 mg, 0.81 mmol, 4.0 eq) and XPhos Pd G3 (17.17 mg, 0.02 mmol, 0.1 eq). The mixture was stirred at 95 °C for 2 hours. The reaction mixture was cooled to room temperature. The mixture was filtered and concentrated under vacuum to give a residue, which was purified by column chromatography (C ₁₈ , 0.1% TFA in water/MeCN) to give the title compound (2.91 mg, yield rate 3%). LCMS: m/z 398.0 [M+H] ⁺ , ESI pos. Example 108 : 4-[2-[[( 1R , 2R )-2-( dimethylamino ) cyclopentyl ] amino ] oxazolo [4,5-b] pyridin -5- yl ] -3- Hydroxy -5- methyl - benzonitrile

step A : N -[(1 R ,2 R )-2-[(5- Chlorazolo [4,5-b] pyridine -2- base ) Amino ] Cyclopentyl ] Tertiary butyl carbamate

To 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (120 mg, 599 µmol, 1.0 eq) and N -[(1 R ,2 R )-2-amino ring To a mixture of tert-butylpentyl]carbamate (155.7 mg, 777 µmol, 1.3 eq) in 1,4-dioxane (1.67 mL) was added triethylamine (108 µL, 777 µmol, 1.3 eq). The reaction mixture was stirred overnight at 120 °C. After cooling to room temperature, it was extracted with EtOAc and water. The aqueous layer was back extracted with EtOAc. The combined organic layers were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product (280 mg) was used in the next step without further purification. LCMS m/z: 353.2 [M+H] ⁺ , ESI pos.

step B : N -[(1 R ,2 R )-2-[[5-(4- cyano -2- hydroxyl -6- methyl - Phenyl ) zozolo [4,5- b ] pyridine -2- base ] Amino ] Cyclopentyl ] Tertiary butyl carbamate

Under argon gas, N -[(1 R ,2 R )-2-[(5-chlorooxazolo[4,5- b ]pyridin-2-yl)amino]cyclopentyl]-amine Tertiary- butyl formate (280 mg, 0.778 mmol, 1.0 eq) and (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid ( Example 25 , step D ) (234 mg, 1.32 mmol, 1.7 eq) To a mixture of 1,4-dioxane (4.8 mL) and water (1.2 mL) was added cesium carbonate (760 mg, 2.33 mmol, 3.0 eq) followed by XPhos Pd G3 (98.75 mg, 116.66 µmol, 0.15 eq). The reaction mixture was stirred at 100°C for 5 hours. The reaction mixture was extracted with ethyl acetate, ammonium chloride and water. The aqueous layer was back extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Gradient: 0% to 50% ethyl acetate in heptane) to afford the title compound (273.1 mg, 77% yield) as a light brown viscous oil. LCMS m/z: 450.3 [M+H] ⁺ , ESI pos.

step C : 4-[2-[[(1 R ,2 R )-2- Aminocyclopentyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-3- hydroxyl -5- methyl - Benzonitrile; 1:1 Hydrochloride

To N -[(1 R ,2 R )-2-[[5-(4-cyano-2-hydroxy-6-methyl-phenyl)oxazolo[4,5- b ]pyridine-2- To a solution of tertiary-butyl]amino] cyclopentyl ]carbamate (273.1 mg, 607.6 µmol, 1.0 eq) in methanol (2.5 mL) and DCM (5 mL) was added dropwise 4 M HCl in distilled water in alkanes (1.52 mL, 6.08 mmol, 10 eq). The reaction was stirred overnight at room temperature under argon gas. The solvent was evaporated in vacuo to give the title compound (233.9 mg, 96%) as an off-white solid. LCMS m/z: 350.2 [M+H] ⁺ , ESI pos.

step D. : 4-[2-[[(1 R ,2 R )-2-( Dimethylamino ) Cyclopentyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-3- hydroxyl -5- methyl - Benzonitrile

To N -[(1 R ,2 R )-2-[[5-(4-cyano-2-hydroxy-6-methyl-phenyl)oxazolo[4,5- b ]pyridine-2- To a suspension of tertiary-butyl]amino]cyclopentyl]carbamate (90 mg, 224 µmol, 1.0 eq) in 1,2-dichloroethane (2.4 mL) was added formaldehyde (408 mg, 36.7 µL, 492.6 µmol, 2.2 eq) and sodium acetate (45.9 mg, 559.8 µmol, 2.5 eq). The mixture was cooled with an ice bath, and sodium triacetoxyborohydride (189.8 mg, 895.7 µmol, 4.0 eq) was added. After 5 minutes, the reaction mixture (still a suspension) was brought to room temperature and stirring was continued for 2 hours. Then, the reaction mixture was extracted with sodium bicarbonate, water and DCM. The aqueous layer was back extracted twice with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product (77 mg, pale yellow powder) was purified via SFC (column: chiral AD-H, 5 µm, 250 x 20 mm, 25% MeOH + 0.2% DEA) to afford the title compound (51 mg, yield 60%). LCMS m/z: 378.3 [M+H] ⁺ , ESI pos. Example 109 : 4-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyrazin -5- yl ]-3- hydroxy -5- methyl - benzonitrile; 2,2,2- trifluoroacetic acid

step A : 3-( Benzyloxy )-6- Chloropyrazine -2- amine

To a stirred solution of benzyl alcohol (4.49 mL, 43.18 mmol, 1.0 eq) in THF (90 mL) at room temperature was added NaH (1.73 g, 43.18 mmol, 1.0 eq, 60%). The mixture was stirred at ambient temperature for 10 minutes. Then 3-bromo-6-chloropyrazin-2-amine (9.0 g, 43.18 mmol, 1.0 eq; CAS: 212779-21-0) was added and the reaction mixture was heated at 70°C for 4 hours. The reaction mixture was cooled to room temperature. Ethyl acetate (60 mL) and water (80 mL) were added and the layers were separated. The aqueous phase was extracted with ethyl acetate (80 mL x 2). The combined extracts were washed with brine (80 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 1:1), and then by normal phase flash chromatography (column: Welch Ultimate XB-CN 250 × 70 × 10um , conditions: hexane-EtOH, B at the start: 12, B at the end: 12; gradient time (min) 15; 100% B hold time (min): 5, flow rate (mL/min): 140) Purified to The title compound was obtained as a yellow solid (2.3 g, 23% yield). LCMS: m/z 236.0 [M+H] ⁺ , ESI pos.

step B : ( R )-3- Isothiocyanatopiperidine -1- Benzyl formate

To a solution of benzyl (R)-3-aminopiperidine-1-carboxylate (1.0 g, 4.27 mmol, 1.0 eq) in DCM (5 mL) was added dropwise in DCM (5 mL) at 0 °C Thiophosgene (0.490 g, 4.27 mmol, 1.0 eq) was added and stirred at 20°C for 2 hours. The above reaction mixture was directly purified by silica gel column (petroleum ether: ethyl acetate = 1:0 to 5:1) to obtain the title compound (0.85 g, 3.08 mmol, yield 72%) as yellow oil. ¹ H NMR (DMSO- d _6, 400 MHz) δ [ppm]: 7.45 - 7.27 (m, 5H), 5.12 (s, 2H), 4.06 - 3.98 (m, 1H), 3.96 - 3.62 (m, 2H) , 3.44 - 3.36 (m, 1H), 3.28 - 2.95 (m, 1H), 1.95 - 1.82 (m, 2H), 1.69 - 1.45 (m, 2H).

step C : ( R )-3-(3-(3-( Benzyloxy )-6- Chloropyrazine -2- base ) Thiourea ) piperidine -1- Benzyl formate

To a solution of 3-(benzyloxy)-6-chloropyrazin-2-amine (0.600 g, 2.55 mmol, 1.0 eq) in THF (6 mL) was added NaH (203.67 mg, 5.09 mmol, 2.0 eq), stirred at 0°C for 0.5 hours, then added ( R )-benzyl 3-isothiocyanatopiperidine-1-carboxylate (0.703 g, 2.55 mmol, 1.0 eq) dropwise at 0°C in THF (3 mL) and continue stirring at 20°C for 1 hour. The above reaction solution was quenched with saturated ammonium chloride (100 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 1: 0 to 5:1) to afford the title compound (0.500 g, 36% yield) as a yellow gum. LCMS: m/z 512.1 [M+H] ⁺ , ESI pos.

step D. : ( R )-1-(6- chlorine -3- Hydroxypyrazine -2- base )-3-( piperidine -3- base ) Thiourea

To ( R )-benzyl 3-(3-(3-(benzyloxy)-6-chloropyrazin-2-yl)thioureido)piperidine-1-carboxylate (0.50 g, 0.98 mmol, 1.0 eq ) in TFA (1.0 mL, 13.2 mmol, 13.47 eq) was added anisole (0.21 mL, 1.95 mmol, 2.0 eq) and stirred at 75°C for 12 hours. The above reaction solution was concentrated under reduced pressure and purified by reverse phase flash chromatography (0.1% TFA, water-ACN) to give the title compound (0.060 mg, yield 12%) as a yellow solid. LCMS: m/z 288.2 [M+H] ⁺ , ESI pos.

step E. : ( R )-1-(6- chlorine -3- Hydroxypyrazine -2- base )-3-(1- Ethylpiperidine -3- base ) Thiourea

To ( R )-1-(6-chloro-3-hydroxypyrazin-2-yl)-3-(piperidin-3-yl)thiourea (0.040 g, 0.1 mmol, 1.0 eq) in methanol (1 mL ) in solution was added TEA (0.020 g, 0.2 mmol, 2.0 eq), stirred for 30 minutes, then added acetic acid (0.030 g, 0.5 mmol, 5.0 eq), 4A MS (0.050 g) and acetaldehyde (0.07 mL, 0.5 mmol, 5.0 eq), stirred at 20°C for 20 minutes. Then, NaBH ₃ CN (0.032 g, 0.5 mmol, 5.0 eq) was added and stirring was continued for 1 hour at 20°C. The reaction mixture was filtered. The filtrate was concentrated. The crude product was purified by reverse phase flash chromatography (0.1% TFA, water-ACN) to afford the title compound (0.040 g, 92% yield) as a yellow solid. LCMS: m/z 315.9 [M+H] ⁺ , ESI pos.

step f : ( R )-5- chlorine -N-(1- Ethylpiperidine -3- base ) zozolo [4,5-b] pyrazine -2- amine

To ( R )-1-(6-chloro-3-hydroxypyrazin-2-yl)-3-(1-ethylpiperidin-3-yl)thiourea (0.030 g, 0.02 mmol, 1.0 eq) and To a mixture of tetrabutylammonium iodide (0.008 g, 0.02 mmol, 1.0 eq) in THF (0.5 mL) _was added _H2O2 (0.005 g, 0.05 mmol, 2.0 eq) and stirred at 25 °C for 2 hours. The above reaction solution was then purified by reverse phase flash chromatography (0.1% TFA, water-ACN) to obtain the title compound (0.020 g, yield 71%) as yellow oil. LCMS: m/z 282.0 [M+H] ⁺ , ESI pos.

step G : 4-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyrazine -5- base ]-3- hydroxyl -5- methyl - Benzonitrile; 2,2,2- Trifluoroacetate

To ( R )-5-chloro- N- (1-ethylpiperidin-3-yl)oxazolo[4,5-b]pyrazin-2-amine ( Example 109 , Step F ) (0.010 g, 0.03 mmol, 1.0 eq) to a solution of 1,4-dioxane (1 mL) and water (0.2 mL) was added (4-cyano-2-hydroxy-6-tolyl)boronic acid (0.004 g, 0.03 mmol, 1.0 eq), CsF (0.009 g, 0.06 mmol, 2.5 eq) and Xphos Pd G3 (0.004g, 0.01 mmol, 0.2 eq), and the above reaction mixture was stirred at 95° C. under N ₂ gas for 2 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (0.1% TFA, water-MeCN) and purified by preparative HPLC (column: Waters Xbridge C ₁₈ 150 × 50 mm × 10 µm; conditions: water (NH ₄ HCO ₃ )-ACN; B at the beginning: 26; B at the end: 56; Gradient time (min): 10; 100% B hold time (min): 2; Flow rate (mL/min): 30), to obtain a white solid The title compound (0.001 g, 7.4% yield). LCMS: m/z 379.1 [M+H] ⁺ , ESI pos. Example 110 : 4-[2-[[(3 R )-1- ethyl - 3- piperidinyl ] amino ] oxazolo [4,5-b] pyridin -5- yl ]-3- hydroxyl- 5-( methoxymethyl ) benzonitrile; 2,2,2- trifluoroacetic acid

step A : 2- Amino -5- bromine -3- Methyl methoxybenzoate

To a solution of methyl 2-amino-3-methoxy-benzoate (10.0 g, 55.2 mmol, 1.0 eq CAS: 5121-34-6) in methanol (40 mL) at 0°C to 10°C A solution of _Br2 (3.4 mL, 66.2 mmol, 1.2 eq) in acetic acid (20 mL) was added dropwise. The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was poured into aqueous NaHSO ₃ (20 mL), and extracted with EtOAc (150 mL×3). The organic phase was washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=100/1 to 5/1) to give the title compound (10.0 g, yield 70%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.43 (d, 1H), 7.10 (d, 1H), 6.46 (br. s, 1H), 3.85 (s, 3H), 3.80 (s , 3H).

step B : 2- Amino -5- cyano -3- Methyl methoxybenzoate

To a solution of 2-amino-5-bromo-3-methoxy-benzoic acid methyl ester (10.0 g, 38.45 mmol, 1.0 eq) in NMP (50 mL) was added CuCN (4.13 g, 46.14 mmol, 1.2 eq). The mixture was stirred at 180 °C for 2 h at MW. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (100 ml × 3). The organic phase was washed with brine (100 mL x 3), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 5:1) to obtain the title compound (6.0 g, yield 76%) as a white solid. LCMS: m/z 207.1 [M+H] ⁺ , ESI pos.

step C : 2- bromine -5- cyano -3- Methyl methoxybenzoate

To 2-amino-5-cyano-3-methoxy-benzoic acid methyl ester (5.7 g, 27.64 mmol, 1.0 eq), CuBr (5.95 g, 41.5 mmol, 1.5 eq) in MeCN (80 mL) Butyl nitrite (4.28 g, 41.5 mmol, 1.5 eq) was added to the solution. The mixture was stirred at 65°C for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with brine (100 mL x 3), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 5:1) to obtain the title compound (4.0 g, yield 54%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.78 (d, 1H), 7.74 (d, 1H), 3.96 (s, 3H), 3.88 (s, 3H).

step D. : 2- bromine -5- cyano -3- Hydroxybenzoic acid

To a solution of methyl 2-bromo-5-cyano-3-methoxy-benzoate (3.8 g, 14.1 mmol, 1.0 eq) in DCM (20 mL) was added BBr ₃ (13.6 mL , 140.7 mmol, 10.0 eq), and then the mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with brine (100 mL x 3), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 2:1) to obtain the title compound (2.9 g, yield 85%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 13.76 (br. s, 1H), 11.41 (s, 1H), 7.52 (d, 1H), 7.33 (d, 1H).

step E. : 2- bromine -5- cyano -3-(2- Trimethylsilylethoxymethoxy )- benzoic acid 2- Trimethylsilylethoxymethyl ester

A solution _of 2-bromo-5-cyano-3-hydroxy-benzoic acid (2.9 g, 11.9 mmol, 1.0 eq), _Cs2CO3 (7.81 g, 23.96 mmol, 2.0 eq) in DMF (50 mL) Stir at 25°C for 10 minutes, then add SEM-Cl (4.0 g, 23.96 mmol, 2.0 eq) and stir at 25°C for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with brine (100 mL x 3), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 2:1) to obtain the title compound (3.60 g, yield 60%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.83 (d, 1H), 7.78 (d, 1H), 5.49 (d, 4H), 3.82 - 3.73 (m, 4H), 0.96 - 0.87 (m, 4H), -0.01 (s, 9H), -0.07 (s, 9H).

step f : 4- bromine -3-( Hydroxymethyl )-5-((2-( Trimethylsilyl ) Ethoxy ) Methoxy ) Benzonitrile

To 2-trimethylsilylethoxymethyl 2-bromo-5-cyano-3-(2-trimethylsilylethoxymethoxy)benzoate (3.0 g, 5.97 mmol, 1.0 eq ) in THF (20 mL) was added NaBH ₄ (903.31 mg, 23.9 mmol, 4.0 eq) and stirred at 25°C for 16 hours. The reaction mixture was poured into water (10 mL), and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with brine (100 mL x 3), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 5:1) to obtain the title compound (1.6 g, yield 75%) as a white solid. ¹ H NMR (CD ₃ OD _, 400 MHz) δ [ppm]: 7.55 (d, 1H), 7.48(d, 1H), 5.65 (t, 1H), 5.43 (s, 2H), 4.52 (d, 2H) , 3.73 (t, 2H), 0.88 (t, 2H), -0.05 (s, 9H).

step G : 4- bromine -3-( Methoxymethyl )-5-((2-( Trimethylsilyl ) Ethoxy ) Methoxy ) Benzonitrile

To 4-bromo-3-(hydroxymethyl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile (200 mg, 0.56 mmol, 1.0 eq) in THF (3 mL) NaH (44.7 mg, 1.12 mmol, 2.0 eq, 60%) was added to the solution and stirred at 25°C for 10 minutes, then MeI (0.1 mL, 1.61 mmol, 2.88 eq) was added and stirred at 25°C for 2 hours. The mixture was quenched with water (30 mL), and extracted with EtOAc (30 mL x 3). The organic phase was washed with brine (30 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc, 50:1 to 10:1) to give the title compound (130 mg, 63% yield) as a colorless oil. ¹ H NMR (DMSO-d _6, 400 MHz) δ [ppm]: 7.60(s, 1H), 7.46 (s, 1H), 5.44 (s, 2H), 4.48 (s, 2H), 3.74 (t, 2H ), 3.39 (s, 1H), 0.88 (t, 2H), -0.04 (s, 9H).

step h : 3-( Methoxymethyl )-4-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base )-5-((2-( Trimethylsilyl ) Ethoxy ) Methoxy ) Benzonitrile

To 4-bromo-3-(methoxymethyl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile (130.0 mg, 0.35 mmol, 1.0 eq), 4,4,4 ',4',5,5,5',5'-Octamethyl-2,2'-bi(1,3,2-dioxaborolane) (441.68 mg, 1.75 mmol, 5.0 eq) To a mixture in 1,4-dioxane (4 mL) was added KOAc (102.8 mg, 1.05 mmol, 3.0 eq) and Pd(dppf)Cl ₂ (25.5 mg, 0.03 mmol, 0.1 eq), and then the mixture was Stir at 95°C for 4 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with brine (100 mL x 3), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 10:1) to obtain the title compound (20.0 mg, yield 14%) as a white solid. ¹ H NMR (CD ₃ OD _, 400 MHz) δ [ppm]: 7.31 (s, 1H), 7.26 (s, 1H), 5.30 (s, 2H), 4.49 (s, 2H), 3.84 - 3.76 (m, 2H), 3.32 (s, 3H), 1.40 (s, 12H), 0.99 - 0.92 (m, 2H), 0.01 (s, 9H).

step I : ( R )-4-(2-((1- Ethylpiperidine -3- base ) Amino ) zozolo [4,5-b] pyridine -5- base )-3 ( Methoxymethyl )-5-((2-( Trimethylsilyl ) Ethoxy ) Methoxy ) Benzonitrile

To (3 S ,5 R )-5-[(5-bromozozolo[4,5-b]pyridin-2-yl)amino]-1-ethyl-piperidin-3-ol; 2, 2,2-Trifluoroacetic acid (28.22 mg, 0.06 mmol, 1.3 eq), 3-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile (20.0 mg, 0.05 mmol, 1.0 eq), K ₂ CO ₃ (16.5 mg, 0.12 mmol, 2.5 eq) To a mixture of 1,4-dioxane (1 mL) and water (0.2 mL) was added XPhos Pd G ₃ (4.01 mg, 0.1 eq) and purged with N ₂ three times. The mixture was heated at 95°C for 2 hours. The mixture was then cooled to 25 °C, concentrated under reduced pressure, and the crude product was purified by column chromatography (C ₁₈ , 0.1% TFA in water/MeCN) to afford the title compound (15.0 mg, yield 85%). LCMS: m/z 538.4 [M+H] ⁺ , ESI pos.

step J : 4-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- hydroxyl -5-( Methoxymethyl ) Benzonitrile; 2,2,2- Trifluoroacetate

To 4-[2-[[(3 R )-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methoxy To a mixture of methyl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile (15.0 mg, 0.03 mmol, 1.0 eq) in DCM (1 mL) was added TFA (27.06 mg, 0.28 mmol, 10.0 eq), and stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure and purified by column chromatography (C ₁₈ , 0.1% TFA in water/MeCN) to afford the title compound (7.7 mg, 52% yield) as a yellow solid. LCMS: m/z 408.1 [M+H]+, ESI pos. Example 111 : 4-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ]-7- methoxy - oxazolo [4,5-b] pyridine -5- base ]-3- hydroxy -5- methyl - benzonitrile; 2,2,2- trifluoroacetic acid

step A : R -5- chlorine - N -(1- Ethylpiperidine -3- base )-7- Iodozozolo [4,5-b] pyridine -2- Amine; Trifluoroacetic acid

To a mixture of R -1-methylpiperidin-3-amine (81.4 mg, 0.64 mmol, 2.5 eq) in MeCN (3 mL) was added 2,5-dichloro-7-iodooxazolo[4, 5-b]pyridine (80.0 mg, 0.25 mmol, 1.0 eq) and DIEA (0.08 mL, 0.51 mmol, 2.0 eq), and the mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with 2 mL of MeOH. The residue was then purified by column chromatography (C ₁₈ , 0.1% TFA in water/MeCN) and purified by preparative HPLC (column: 3_Phenomenex Luna C ₁₈ 75×30 mm×3 um; condition : Water (TFA)-CAN; B at start: 15; B at end: 35; Gradient time (min): 9; 100% B hold time (min): 2; Flow rate (ml/min): 25) Purify again , to afford the title compound (70.0 mg, 68% yield, TFA salt) as a yellow solid. LCMS: m/z 407.1 [M+H] ⁺ , ESI pos.

step B : R -5- chlorine - N -(1- Ethylpiperidine -3- base )-7- Methoxyzolo [4,5-b] pyridine -2- amine

1,10-phenanthroline (3.46 mg, 0.02 mmol, 0.2 eq), R -5-chloro- N- (1-ethylpiperidin-3-yl)-7-iodozozolo[4,5-b ]pyridin-2-amine; trifluoroacetic acid (50.0 mg, 0.1 mmol, 1.0 eq), Cs ₂ CO ₃ (62.42 mg, 0.19 mmol, 2.0 eq) and CuI (1.82 mg, 0.01 mmol, 0.1 eq) in methanol ( 0.5 mL) of the mixture. _N2 was bubbled through the reaction mixture for 3 min. The reaction vessel was then sealed and heated in the microwave at 110°C for 60 minutes. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (C ₁₈ , 0.1% TFA in water/MeCN) and purified by column chromatography (C ₁₈ , 0.1% NH ₃ ·H ₂ O in water/MeCN ) was purified again to give the title compound (10.0 mg, 26% yield) as a yellow oil. LCMS: m/z 311.1 [M+H]+, ESI pos.

step C : 4-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ]-7- Methoxy - zozolo [4,5-b] pyridine -5- base ]-3- hydroxyl -5- methyl - Benzonitrile; 2,2,2- Trifluoroacetate

To (4-cyano-2-hydroxy-6-methylphenyl)boronic acid (13.67 mg, 0.08 mmol, 3.0 eq) and R -5-chloro- N- (1-ethylpiperidine) under N ₂ -3-yl)-7-methoxyoxazolo[4,5-b]pyridin-2-amine (8.0 mg, 0.03 mmol, 1.0 eq) in 1,4-dioxane (1 mL) and water (0.2 mL) were added CsF (20.0 mg, 0.13 mmol, 5.11 eq) and XPhos Pd G3 (2.18 mg, 0.0 mmol, 0.1 eq). The mixture was stirred at 95 °C for 2 hours. Then, the reaction mixture was cooled to room temperature. EtOAc (10 mL) and water (10 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (10 mL x 2). The combined extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was subjected to preparative HPLC (method: column: Waters Xbridge 150 × 25 mm × 5 um; condition: water (NH ₄ HCO ₃ )-ACN; B at the beginning: 36; B at the end: 66; gradient time (minutes): 9; 100% B retention time (minutes): 2; flow rate (ml/min): 25) Purification. After lyophilization, the compound was subjected to preparative HPLC (method: column: YMC Triart C ₁₈ 150 × 25 mm × 5 um; condition: water (TFA)-ACN, B at the beginning: 19; B at the end: 39; Gradient time (min): 10; 100% B hold time (min): 2; flow rate (ml/min): 25) Purified again to give the title compound (1.06 mg, 10% yield) as a yellow solid. LCMS: m/z 408.1 [M+H] ⁺ , ESI pos. Example 112 : 5- Chloro -2-[2-[[( 1R , 2R )-2-( dimethylamino ) cyclopentyl ] amino ] oxazolo [4,5-b ] pyridine- 5- yl ]-3- methyl - phenol

step A : N -[(1 R ,2 R )-2-[(5- Chlorazolo [4,5-b] pyridine -2- base ) Amino ] Cyclopentyl ] Tertiary butyl carbamate

According to GP1 , 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (115 mg, 573.1 µmol, 1.0 eq) was mixed with N -[(1 R ,2 R )-2- Aminocyclopentyl]carbamate (126.27 mg, 630.45 µmol, 1.1 eq) was reacted to give the title compound as light brown crystals (240 mg, 107%) which were used in the next step without further purification.

step B : N -[(1 R ,2 R )-2-[[5-(4- chlorine -2- hydroxyl -6- methyl - Phenyl ) zozolo [4,5-b] pyridine -2- base ] Amino ] Cyclopentyl ] Tertiary butyl carbamate

According to GP2a , N -[(1 R ,2 R )-2-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]cyclopentyl]-carbamic acid tertiary Butyl ester (240 mg, 612.2 µmol, 1.0 eq) was reacted with (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid ( CAS # 1207961-50-9 ) to give the title compound as a pale yellow solid (195.1 mg, 62%). LCMS: 459.3 [M+H] ⁺ , ESI pos.

step C : 2-[2-[[(1 R ,2 R )-2- Aminocyclopentyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-5- chlorine -3- methyl - phenol

To N -[(1 R ,2 R )-2-[[5-(4-chloro-2-hydroxyl-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl ]Amino]cyclopentyl]carbamate tert-butyl ester (190.5 mg, 373.58 umol, 1.0 eq) in DCM (3.2 mL) and methanol (1.6 mL) was added dropwise with 4 M HCl in dioxane Medium (1.11 g, 0.9 mL, 3.74 mmol, 10 eq). The reaction mixture was stirred at room temperature under argon atmosphere for 4.5 hours. Solvent was removed under reduced pressure. Then, the residue was dissolved in water and extracted with DCM. The organic phase was then washed with sodium bicarbonate and water. The aqueous layer was extracted again with DCM. The combined organic layers were washed with water and brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Gradient: 0% to 80% DCM:MeOH:NH ₄ OH (110:10:1 ) in DCM) to afford the title compound (93.7 mg, 69% ). LCMS: 359.1 [M+H] ⁺ , ESI pos.

step D. : 5- chlorine -2-[2-[[(1 R ,2 R )-2-( Dimethylamino ) Cyclopentyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- methyl - phenol

According to GP4 , the above 2-[2-[[(1R,2R)-2-aminocyclopentyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro- 3-Methyl-phenol was reacted to give the title compound, which was purified by HPLC chromatography (column: Gemini NX, 12 nm, 5 µm, 100 × 30 mm; MeCN/(water+0.1% TEA)) to give a white powder The title compound (34.3 mg, 40%). LCMS: 385.3 [MH] ^- , ESI neg. Example 113 : 5- Chloro -2-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyrazin -5- yl ] -3- methyl - phenol; 2,2,2- trifluoroacetic acid

To the above ( R )-5-chloro-N-(1-ethylpiperidin-3-yl)oxazolo[4,5-b]pyrazin-2-amine ( Example 109 , Step F ) (0.010 g , 0.03 mmol, 1.0 eq) to a solution of 1,4-dioxane (1 mL) and water (0.2 mL) was added (4-chloro-2-hydroxy-6-tolyl)boronic acid (0.005 g, 0.03 mmol, 1.0 eq), CsF (0.009 g, 0.06 mmol, 2.5 eq) and XPhos Pd G3 (0.004 g, 0.01 mmol, 0.2 eq). The above reaction mixture was then stirred at 90 °C for 2 hours under nitrogen atmosphere. The above reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated. The crude product was then purified by reverse phase flash chromatography (0.1% TFA, water-MeCN) to afford the title compound (0.002 g, 19% yield) as a yellow solid. LCMS: m/z 388.1 [M+H]+, ESI pos. Example 114 : 5- Chloro -2-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridin -5- yl ]- 3-( trifluoromethoxy ) phenol; 2,2,2- trifluoroacetic acid

step A : 4- chlorine -2- iodine -6-( Trifluoromethoxy ) aniline

To a solution of 4-chloro-2-(trifluoromethoxy)aniline (CAS # 175205-77-3, 9.10 g, 43.0 mmol, 1.0 eq) in acetic acid (50 mL) was added N -iodo at 0 °C Succinimide (9.6 g, 42.7 mmol, 0.99 eq) was then stirred at 20°C for 3 hours. The above reaction solution was diluted with water (200 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated NaHCO ₃ solution (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 100:1) to obtain the title compound (10.0 g, yield 69%) as yellow oil. ¹ H NMR (CDCl ₃ , 400 MHz) δ [ppm]: 7.59 (d, 1H), 7.16 (d, 1H), 4.36 (br s, 2H).

step B : 2-( Benzyloxy )-4- chlorine -6-( Trifluoromethoxy ) aniline

To a solution of benzyl alcohol (5.77 g, 53.3 mmol, 3.0 eq) in _toluene (120 mL) was added _Cs2CO3 (17.4 g, 53.3 mmol, 3.0 eq) and stirred at 20 °C for 30 min. Then 4-chloro-2-iodo-6-(trifluoromethoxy)aniline (6.0 g, 17.8 mmol, 1.0 eq), 1,10-phenanthroline (0.64 g, 3.56 mmol, 0.2 eq), CuI ( 0.34 g, 1.78 mmol, 0.1 eq), and stirred at 110°C for 12 hours. The above reaction solution was diluted with water (200 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 50:1) to obtain a black oil, which was then purified by reverse phase flash chromatography (0.1% TFA, (H2O-MeCN) to afford the title compound (2.2 g, 39% yield) as a yellow solid. LCMS: m/z 318.0 [M+H]+, ESI pos.

step C : 1-( Benzyloxy )-5- chlorine -2- iodine -3-( Trifluoromethoxy ) benzene

To a mixture of 2-(benzyloxy)-4-chloro-6-(trifluoromethoxy)aniline (0.70 g, 2.2 mmol, 1.0 eq) in HCl (7.0 mL, purity 37%) at 0°C Add a solution of NaNO ₂ (0.30 g, 4.41 mmol, 2.0 eq) in water (3 mL), stir at 0°C for 0.5 h, then add KI (1.46 g, 8.81 mmol, 4.0 eq) in water dropwise at 0°C (4 mL) and stirred at 20°C for 12 hours. The mixture was quenched with saturated sodium sulfite (50 mL), extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:0 to 20:1) to give the title compound (0.30 g, yield 32%) as a yellow solid. ¹ H NMR (CDCl ₃ , 400 MHz) δ [ppm]: 7.53 - 7.48 (m, 2H), 7.47 - 7.40 (m, 2H), 7.39 - 7.33 (m, 1H), 7.00 - 6.95 (m, 1H) , 6.82 (d, 1H), 5.18 (s, 2H).

step D. : 2-(2-( Benzyloxy )-4- chlorine -6-( Trifluoromethoxy ) Phenyl )-4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane

To a solution of 1-(benzyloxy)-5-chloro-2-iodo-3-(trifluoromethoxy)benzene (0.20 g, 0.47 mmol, 1.0 eq) in THF (1 mL) was added 2- Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.22 mg, 1.18 mmol, 2.53 eq), then add iprMgCl dropwise at -5°C -LiCl (0.54 mL, 0.7 mmol, 1.5 eq), then stirred at 20°C for 1 hour. The above reaction solution was quenched with saturated NH ₄ Cl solution (50 mL) at 0°C, and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 50:1) to obtain the title compound (30.0 mg, yield 15%) as a yellow solid. ¹ H NMR (CDCl ₃ , 400 MHz) δ [ppm]: 7.47 - 7.43 (m, 2H), 7.41 - 7.30 (m, 3H), 6.89 (s, 1H), 6.85 (s, 1H), 5.05 (s , 2H), 1.30 (s, 12H).

step E. : ( R )-5-(2-( Benzyloxy )-4- chlorine -6-( Trifluoromethoxy ) Phenyl )-N-(1- Ethylpiperidine -3- base ) zozolo [4,5-b] pyridine -2- amine

To 2-(2-(benzyloxy)-4-chloro-6-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa To a solution of cyclopentaborane (0.030 g, 0.07 mmol, 1.0 eq) in 1,4-dioxane (1 mL) and water (0.2 mL) was added ( R )-5-bromo-N-(1- Ethylpiperidin-3-yl)oxazolo[4,5-b]pyridin-2-amine (0.031 g, 0.07 mmol, 1.0 eq), CsF (0.026 g, 0.17 mmol, 2.5 eq) and XPhos Pd G3 (0.012 g, 0.01 mmol, 0.2 eq), then the above reaction mixture was stirred at 90 °C for 1 h under N ₂ gas. After cooling to ambient temperature, it was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (DCM:MeOH=10:1, Rf=0.1) to give the title compound (0.020 mg, yield 29%) as a yellow gum. LCMS: m/z 547.3 [M+H]+, ESI pos.

step f : 5- chlorine -2-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3-( Trifluoromethoxy ) phenol; 2,2,2- Trifluoroacetate

( R )-5-(2-(benzyloxy)-4-chloro-6-(trifluoromethoxy)phenyl)-N-(1-ethylpiperidin-3-yl)oxazolo A solution of [4,5-b]pyridin-2-amine (0.010 mg, 0.02 mmol, 1.0 eq) in TFA (0.5 mL, 6.73 mmol, 368 eq) was stirred at 75°C for 12 hours. After cooling to ambient temperature, it was concentrated under reduced pressure. The residue was subjected to preparative HPLC (column 3_Phenomenex Luna C ₁₈ 75 × 30 mm × 3 um; condition: water (TFA)-MeCN; B at the beginning: 29; B at the end: 49; Gradient time (minutes): 10; 100% B hold time (min): 2; flow rate (ml/min): 25) Purified to give a yellow solid. Then the above yellow solid was subjected to preparative HPLC (column: Waters Xbridge C ₁₈ 150 × 50 mm × 10 um; condition: water (NH4HCO3)-MeCN; B at the beginning: 50; B at the end: 80; gradient time ( min): 10; 100%B hold time (min): 2; flow rate (mL/min): 30) was purified to afford the title compound (1.33 mg, 12% yield) as a white solid. LCMS: m/z 457.1 [M+H] ⁺ , ESI pos. Example 115 : 3- Hydroxy -5- methyl -4-[2-[[( 2S )-2- hydroxy -1,2,3,5,6,7,8,8a -swainsonine -8 -yl ] amino ] oxazolo [4,5-b] pyridin -5- yl ] benzonitrile; 2,2,2- trifluoroacetic acid

step A : (2- Pyridine bromide -3- base ) Tertiary butyl carbamate

To a solution of 2-bromopyridin-3-amine (10.0 g, 57.8 mmol, 1.0 eq) in THF (200 mL) was added LiHMDS (115.6 mL, 115.6 mmol, 2.0 eq) dropwise at 0 °C, followed by After stirring for 0.5 h at 0 °C, a solution of di-tertiary-butyl dicarbonate (13.3 g, 60.7 mmol, 1.05 eq) in THF (10 mL) was added slowly at 0 °C. The reaction mixture was stirred at 20 °C for 12 hours. The above reaction solution was quenched with saturated ammonium chloride (500 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 2:1) to obtain the title compound (12.0 g, yield 70%) as yellow oil. LCMS: m/z 275.0 [M+H] ⁺ , ESI pos.

step B : (2- Allylpyridine -3- base ) Tertiary butyl carbamate

To a solution of tert-butyl (2-bromopyridin-3-yl) carbamate (5.0 g, 18.31 mmol, 1.0 eq) in MeCN (400 mL) was added 2-allyl-4,4,5, 5-Tetramethyl-1,3,2-dioxaborolane (6.15 g, 36.61 mmol, 2.0 eq), Pd(dppf)Cl ₂ (0.67 g, 0.92 mmol, 0.05 eq) and CsF (6.95 g, 45.77 mmol, 2.5 eq), then stirred at 70°C for 2 hours. The above reaction solution was diluted with water (300 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 5:1) to obtain the title compound (3.80 g, yield 86%) as yellow oil. LCMS: m/z 235.0 [M+H] ⁺ , ESI pos.

step C : (S)-(2-(2,3- Dihydroxypropyl ) pyridine -3- base ) Tertiary butyl carbamate

To a solution of tertiary -butyl (2-allylpyridin-3-yl)carbamate (1.0 g, 4.27 mmol, 1.0 eq) in tertiary -butanol (40 mL) and water (40 mL) was added AD-mixture-α (8.31 g, 10.67 mmol, 2.5 eq) and methanesulfonamide (406.0 mg, 4.27 mmol, 1.0 eq). Stirring was continued for 4 hours at 20°C, then another batch of AD-mixture-α (8.31 g, 10.67 mmol, 2.5 eq) was added and the reaction was stirred at 20°C for 12 hours. The above reaction solution was quenched with sodium sulfite (150 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 10:1) to obtain the title compound (600.0 mg, yield 52%) as a yellow solid. LCMS: m/z 269.1 [M+H] ⁺ , ESI pos.

step D. : ( S )-8-(( Level three - Butoxycarbonyl ) Amino )-2- hydroxyl -2,3- Dihydro -1H- Indazine -4- Onium chloride

To a solution of tert-butyl (S)-(2-(2,3-dihydroxypropyl)pyridin-3-yl) carbamate (600.0 mg, 2.24 mmol, 1.0 eq) in DCM (9 mL) TEA (250.0 mg, 2.47 mmol, 1.1 eq) was added followed by ethanesulfonyl chloride (0.2 mL, 2.1 mmol, 0.94 eq) in DCM (3 mL) at 0 °C, then stirred at 20 °C for 2 hours. The solvent of the reaction solution was removed by nitrogen flow to give a white solid, which was then purified by reverse phase flash chromatography (neutral, water-MeCN). Then, the solvent was removed by lyophilization to give the title compound (300 mg, 47% yield) as a yellow gum. LCMS: m/z 251.0 [M+H] ⁺ , ESI pos.

step E. : ((2 S )-2- Hydroxyswainsonine -8- base ) Tertiary butyl carbamate hydrochloride

To ( S )-8-(( tertiary -butoxycarbonyl)amino)-2-hydroxy-2,3-dihydro-1H-indolizin-4-ium chloride (300 mg, 1.05 mmol, 1.0 eq) To a solution in methanol (2 mL) was added PtO ₂ (47.5 mg, 0.21 mmol, 0.2 eq), then stirred at 20° C. under H ₂ gas for 2 hours. The above reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (250 mg, 0.85 mmol, crude product) as a yellow oil. ¹ H NMR (CD ₃ OD _, 400 MHz) δ [ppm]: 4.71 - 4.42 (m, 2H), 4.19 - 3.93 (m, 1H), 3.54 - 3.40 (m, 1H), 3.35- 3.34 (m, 3H ), 2.60 - 2.39 (m, 1H), 2.00 - 1.64 (m, 5H), 1.46 (s, 9H).

step f : (2 S )-8- Aminoswainsonine -2- Alcohol hydrochloride

(( 2S )-2-Hydroxyswainson-8-yl) carbamate tert-butyl hydrochloride (250.0 mg, 0.85 mmol, 1.0 eq) in 1,4-dioxane (1 mL) To the solution in HCl/dioxane (2.19 mL, 8.75 mmol, 10.25 eq) was added and stirring was continued at 20 °C for 2 hours. The above reaction mixture was concentrated under reduced pressure to give the title compound (250 mg, crude product) as a yellow oil. ¹ H NMR (CD ₃ OD _, 400 MHz) δ [ppm]: 4.44 - 4.34 (m, 1H), 3.77 - 3.67 (m, 1H), 3.58 - 3.42 (m, 1H), 3.20 - 3.05 (m, 2H ), 2.97 - 2.95 (m, 2H), 1.86 - 1.63 (m, 4H), 1.58 - 1.42 (m, 2H).

step G : (2 S )-8-((5- bromozolo [4,5-b] pyridine -2- base ) Amino ) Swainsonine -2- alcohol 2,2,2- Trifluoroacetate

To a solution of ( 2S )-8-aminoswainson-2-ol hydrochloride (250.0 mg, 1.3 mmol, 1.0 eq) in 1,4-dioxane (2 mL) was added DIPEA ( 836.84 mg, 6.49 mmol, 5.0 eq). Subsequently, 5-bromo-2-chlorooxazolo[4,5-b]pyridine (272.59 mg, 1.17 mmol, 0.9 eq) in 1,4-dioxane (2 mL) was added dropwise at 0 °C solution, and the above reaction mixture was stirred at 20 °C for 2 hours under nitrogen. The above reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (0.1% TFA, water-MeCN), then the solvent was removed by lyophilization to give the title compound (50.0 mg, 8% yield) as a yellow oil. LCMS: m/z 355.0 [M+H]+, ESI pos.

step h : 3- hydroxyl -5- methyl -4-[2-[[(2 S )-2- hydroxyl -1,2,3,5,6,7,8,8a- Swainsonine -8- base ] Amino ] zozolo [4,5-b] pyridine -5- base ] Benzonitrile ; 2,2,2- Trifluoroacetate

(2 S )-8-((5-bromoazolo[4,5-b]pyridin-2-yl)amino)swainson-2-ol 2,2,2-trifluoroacetate (20.0 mg, 0.04 mmol, 1.0 eq) to a solution in 1,4-dioxane (1 mL) and water (0.2 mL) was added (4-cyano-2-hydroxy-6-tolyl)boronic acid ( 7.6 mg, 0.04 mmol, 1.0 eq), CsF (16.0 mg, 0.11 mmol, 2.46 eq) and XPhos Pd G3 (7.0 mg, 0.01 mmol, 0.19 eq). The reaction mixture was stirred at 95 °C under nitrogen for 2 hours, then cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (0.1% TFA, water-MeCN). The solvent was removed by lyophilization, and the yellow solid was subjected to preparative HPLC (column YMC Triart C ₁₈ 150 × 25 mm × 5 µm; conditions: water (TFA)-MeCN; start B: 22; end B: 42; Gradient Time (min): 10; 100% B Hold Time (min): 2; Flow Rate (mL/min): 25) Purification to give the title compound (1.93 mg, 8% yield) as a yellow gum. LCMS: m/z 406.1 [M+H] ⁺ , ESI pos. Example 116 : 2-[7-( Dimethylamino )-2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridine -5- yl ]-3- methyl -5-( trifluoromethyl ) phenol

step A : (3 R )-3-[[7- bromine -5-[2- Methoxy -6- methyl -4-( Trifluoromethyl )- Phenyl ] zozolo [4,5-b] pyridine -2- base ] Amino ] piperidine -1- Tertiary butyl formate

(3 R )-3-[[5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-4-oxanionyl-oxazolo[4,5- b] Pyridin-4-ium-2-yl]amino]piperidine-1- carboxylic acid tert-butyl ester ( Example 103 , Step B ) (580 mg, 1.11 mmol, 1.0 eq) was dissolved in DMF (20 mL) , and oxalyl bromide (0.95 mL, 6.66 mmol, 6.0 eq) was added under vigorous stirring at 0 °C. The mixture was stirred at room temperature for 20 min, then 2 N aqueous NaOH (2 mL) was added. The mixture was diluted with EtOAc (50 mL) and washed with 10 wt% aqueous LiCl (3 x 50 mL), dried using a phase separator, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (24 g column, 0% to 7% MeOH/DCM) to afford the title compound (250 mg, 31% yield) as a pale yellow solid. LCMS m/z 585.1 ( ⁷⁹ Br) [M+H] ⁺ , ESI pos.

step B : (3 R )-3-[[7-( Dimethylamino )-5-[2- Methoxy -6- methyl -4-( Trifluoromethyl )- Phenyl ] zozolo [4,5-b] pyridine -2- base ] Amino ] piperidine -1- Tertiary butyl formate

Dimethylamine (2 M in THF) (2.0 mL, 4.0 mmol, 38.26 eq), RuPhos Pd G3 (26.23 mg, 0.03 mmol, 0.3 eq), (3 R )-3-[[7-bromo -5-[2-Methoxy-6-methyl-4-(trifluoromethyl)-phenyl]oxazolo[4,5-b]pyridin-2-yl]amino]piperidine-1 - tertiary butyl formate (72.0 mg, 0.1 mmol, 1.0 eq) and Cs ₂ CO ₃ (136.3 mg, 0.42 mmol, 4.0 eq) were combined in a sealed vial. It was then heated to 90°C for 2 hours in a microwave reactor. The reaction mixture was dry loaded onto silica and purified by flash chromatography (silica gel, 0% to 10% (0.7 N ammonia in MeOH)/DCM) to give the title compound (62.0 mg, yield rate 90%). LCMS m/z 550.5 [M+H] ⁺ , ESI pos.

step C : 2-[7-( Dimethylamino )-2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

(3 R )-3-[[7-(dimethylamino)-5-[2-methoxy-6-methyl-4-(trifluoromethyl)phenyl]-oxazolo[ 4,5-b]pyridin-2-yl]amino]piperidine-1- carboxylic acid tert-butyl ester (70.0 mg, 0.11 mmol, 1.0 eq) was dissolved in DCM (4 mL) and boron tribromide was added (1 M in DCM) (0.53 mL, 0.53 mmol, 5.0 eq). The mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The resulting residue was dissolved in 0.7 N ammonia in MeOH (5 mL), then concentrated in vacuo. The resulting residue was dissolved in EtOH (4 mL), and one drop of AcOH was added, followed by acetaldehyde (0.02 mL, 0.42 mmol, 4.0 eq). The reaction was stirred for 1 hour, then STAB (89.62 mg, 0.42 mmol, 4.0 eq) was added. The reaction was stirred for 1 h, then wet MeOH (5 mL) was added, and the mixture was allowed to stand for 16 h. The reaction mixture was dry loaded onto silica and purified by silica gel flash chromatography (4 g column, 0% to 15% (0.7 N ammonia in MeOH)/DCM) to give an orange solid (40 mg) . It was dissolved in DMSO (1 mL), filtered and supplemented by reverse phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organizer, Waters 515 ACD Pump, Waters 515 pump, Waters 2998 photodiode array detector, Waters QDa) were purified on a Waters XBridge BEH C18 ODB preparative column (130 Å, 5 µm, 30 mm × 100 mm) (flow rate 40 mL·min ^-1 , Elution was performed with a gradient of 0.3% ammonia in water-MeCN over 12.5 min, UV at all wavelengths obtained using PDA and QDA and ELS detectors). Throughout the method, the on-column dilution pump delivered 2 mL·min ⁻¹ methanol, which is contained in the following MeCN percentages. Gradient profile: 0.0 min to 0.5 min, 40% MeCN; 0.5 min to 10.5 min, increasing from 40% MeCN to 70% MeCN; 10.5 min to 10.6 min, increasing from 70% MeCN to 100% MeCN; 10.6 min to 12.5 min , kept at 100% MeCN. The title compound was thus obtained as an off-white solid (7.2 mg, 15% yield). LCMS m/z 464.5 [M+H]+, ESI pos. Example 117 : 2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ]-5-[2- hydroxy- 6- methyl -4( trifluoromethyl ) phenyl ]- Zazolo [4,5-b] pyridine -7- carbonitrile

Potassium ferrocyanide trihydrate (74.3 mg, 0.18 mmol, 4.0 eq), 2-[7-chloro-2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazole [4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol ( Example 101 , Step A ) (25.0 mg, 0.04 mmol, 1.0 eq), Pd-117 (CAS # 205319-06-8, 23.6 mg, 0.03 mmol, 0.75 eq) and KOAc (8.62 mg, 0.13 mmol, 3.0 eq) were suspended in 1,4-dioxane (1 mL), and water (0.5 mL). The reaction mixture was degassed ( _N2 , 5 min) and then stirred at 90 °C for 6 h. The reaction mixture was concentrated in vacuo, and the resulting residue was dissolved in 20% MeOH in DCM (20 mL), then filtered through a plug of silica. The filtrate was concentrated in vacuo. The resulting residue was dissolved in DMSO (1 mL), filtered and analyzed by reverse phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters System Fluidic Organizer, Waters 515 ACD Pump, Waters 515 Supplemental Pump, Waters 2998 Photodiode Array Detector, Waters QDa) were purified on a Waters XBridge BEH C ₁₈ ODB preparative column (130 Å, 5 µm, 30 mm × 100 mm) at a flow rate of 40 mL min ^-1 , eluted with a gradient of 0.3% ammonia in water-MeCN over 12.5 min, UV at all wavelengths obtained using PDA and QDA and ELS detectors). Throughout the method, the on-column dilution pump delivered 2 mL·min ⁻¹ methanol, which is contained in the following MeCN percentages. Gradient profile: 0.0 min to 0.5 min at 25% MeCN; 0.5 min to 10.5 min in increments from 25% MeCN to 55% MeCN; 10.5 min to 10.6 min in increments from 55% MeCN to 100% MeCN; 10.6 min to 12.5 min , kept at 100% MeCN. The title compound was thus obtained as a light yellow solid (2.7 mg, yield 13%). LCMS m/z 446.4 [M+H] ⁺ , ESI pos. Examples 118a and 118b : 5- Chloro -2-[2-[[(3 R )-1-[[ rac trans -2- hydroxycyclobutyl ] methyl ]-3- piperidinyl ] amino ] oxazolo- [4,5- b ] pyridin -5- yl ]-3- methyl - phenol or 5- chloro -2-[2-[[(3 R )-1-[[ racemic cis Formula -2- hydroxyl - cyclobutyl ] methyl ]-3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridin - 5- yl ]-3- methyl - phenol and 5- chloro -2-[2-[[(3 R )-1-[[ racemic trans -2- hydroxycyclobutyl ] methyl ]-3- piperidinyl ] amino ] oxazolo- [4, 5- b ] pyridin -5- yl ]-3- methyl - phenol or 5- chloro -2-[2-[[(3 R )-1-[[ racemic cis - 2- hydroxy - cyclobutane Base ] methyl ]-3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridin -5- yl ]-3- methyl - phenol

step A : 2-[[(3 R )-3-[(5- bromozolo [4,5- b ] pyridine -2- base ) Amino ]-1- piperidinyl ] methyl ] Cyclobutanone

A solution of (2-oxetanyl)methyl methanesulfonate (150 mg, 0.84 mmol, 1.0 eq) in MeCN (3 mL) was added dropwise to 5-bromo- N -[( 3R )- 3-piperidinyl]oxazolo[4,5- b ]pyridin-2-amine; dihydrochloride ( Example 75 , Step B ) (307 mg, 0.83 mmol, 1.0 eq) and cesium carbonate (1.11 g, 3.39 mmol, 4.1 eq) in MeCN (5 mL) and stirring was continued overnight (16 h) at room temperature. Then, cesium carbonate (270 mg, 0.83 mmol, 1.0 eq) and (2-oxetanyl)methyl mesylate (50.0 mg, 0.28 mmol, 0.34 eq) in MeCN (1 mL) were added, The reaction was stirred for an additional hour. The reaction was concentrated under reduced pressure and loaded onto silica. The crude reaction mixture was purified by column chromatography (Silica, 40 g, 0% to 10% MeOH (0.7M _NH3 ):EtOAc) to give the title compound (167.0 mg, 52% yield) as a colorless gum ). LCMS m/z: 379.2; 381.2 (br isotope) [M+H]+, ESI pos.

step B : 2-[[(3 R )-3-[[5-(4- chlorine -2- hydroxyl -6- methyl - Phenyl ) zozolo [4,5-b] pyridine -2- base ] Amino ]-1- piperidinyl ] methyl ] Cyclobutanone

The above 2-[[(3 R )-3-[(5-bromozozolo[4,5-b]pyridin-2-yl)amino]-1-piperidinyl]methyl]-cyclobutane Ketone (162 mg, 0.43 mmol, 1.0 eq), (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (93.0 mg, 0.5 mmol, 1.17 eq) and potassium carbonate (120.0 mg, 0.87 mmol, 2.03 eq) A solution in 1,4-dioxane (3 mL)) and water (1 mL) was bubbled with N ₂ for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (16.0 mg, 0.02 mmol, 0.05 eq) was added and the reaction mixture was heated to 90°C for 18 hours. The reaction was cooled to room temperature. After bubbling for 5 minutes, (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (16.0 mg, 0.09 mmol, 0.2 eq) and potassium carbonate (30.0 mg, 0.22 mmol, 0.51 eq) were added, Then [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (6.0 mg, 0.01 mmol, 0.02 eq) was added. The reaction was heated to 90 °C for a further 1 hour. The reaction mixture was cooled and concentrated directly onto silica under reduced pressure. The crude reaction mixture was purified by column chromatography (on silica, 0% to 15% MeOH:EtOAc) to afford the title compound (102 mg, 38% yield) as a brown solid. LCMS m/z 441.3; 443.4 (Cl isotope) [M+H]+, ESI pos.

step C : 5- chlorine -2-(2-(((3 R )-1-((2- Hydroxycyclobutyl ) methyl ) piperidine -3- base ) Amino ) zozolo [4,5-b] pyridine -5- base )-3- methyl - phenol

2-[[(3 R )-3-[[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridine-2- Amino]-1-piperidinyl]methyl]cyclobutanone (95.0 mg, 0.22 mmol, 1.0 eq) To a stirred solution of THF (4 mL) was added sodium borohydride (25.0 mg, 0.66 mmol, 3.07 eq), and the reaction was stirred at room temperature for 30 minutes. The reaction was quenched with 1 M HCl (approximately 500 µL), and the reaction was stirred for 15 minutes. MeOH (0.5 mL) was then added, and the reaction mixture was stirred at 50 °C for 4 hours, then at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was subjected to reverse phase preparative HPLC (Waters XBridge BEH C ₁₈ ODB preparative column, 130 Å, 5 µm, 30 mm × 100 mm, flow rate 40 mL/min; Gradient profile: 0.0 to 0.5 minutes with 25% MeCN; 0.5 minutes to 10.5 minutes with increments from 25% MeCN to 55% MeCN; 10.5 minutes to 10.6 minutes with increments from 55% MeCN to 100% MeCN; 10.6 minutes to 12.5 minutes with kept at 100% MeCN) to give 118b (9.57 mg, 10% yield) and 118a (1.81 mg, 1.9% yield). LCMS ( 118b ) m/z 433.4; 345.4 (Cl isotope) [M+H] ⁺ , ESI pos. ¹ H NMR (500 MHz, MeOD) δ [ppm]: 7.67 (dd, 1H), 7.01 (d, 1H), 6.82 (d, 1H), 6.78 (d, 1H), 4.04 – 3.95 (m, 1H) , 3.80 – 3.70 (m, 1H), 3.16 – 3.03 (m, 1H), 2.82 – 2.71 (m, 1H), 2.70 – 2.60 (m, 1H), 2.51 – 2.44 (m, 1H), 2.44 – 2.34 ( m, 1H), 2.34 – 2.22 (m, 2H), 2.22 – 2.15 (m, 1H), 2.11 (s, 3H), 2.06 – 2.01 (m, 1H), 1.93 – 1.81 (m, 2H), 1.81 – 1.75 (m, 1H), 1.75 – 1.66 (m, 1H), 1.58 – 1.45 (m, 1H), 1.24 – 1.13 (m, 1H).

LCMS ( 118a ) m/z 433.4; 345.4 (Cl isotope) [M+H] ⁺ , ESI pos. ¹ H NMR (500 MHz, MeOD) δ [ppm]: 7.67 (d, 1H), 7.01 (d, 1H), 6.82 (dd, 1H), 6.78 (d, 1H), 4.44 – 4.34 (m, 1H) , 4.01 – 3.95 (m, 1H), 3.14 – 3.04 (m, 1H), 2.98 – 2.91 (m, 1H), 2.86 – 2.69 (m, 2H), 2.59 – 2.51 (m, 1H), 2.34 – 2.18 ( m, 3H), 2.11 (s, 3H), 2.09 – 1.98 (m, 2H), 1.91 – 1.80 (m, 2H), 1.75 – 1.60 (m, 2H), 1.57 – 1.47 (m, 1H). Example 119 : 2-[2-[[(3 R )-1- ethyl - 3- piperidinyl ] amino ] oxazolo [4,5-b] pyridin -5- yl ]-3- hydroxyl- Benzonitrile

step A : 2-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- Methoxy - Benzonitrile

2-(5,5-Dimethyl-1,3,2-dioxaborin-2-yl)-3-methoxy-benzonitrile (CAS 3 214360-47-1, 50.0 mg , 0.2 mmol, 1.1 eq), 5-bromo- N -[(3 R )-1-ethyl-3-piperidinyl] oxazolo[4,5- b ]pyridin-2-amine ( example 21 , Step H ) (60.0 mg, 0.18 mmol, 1.0 eq), cesium carbonate (180.0 mg, 0.55 mmol, 3.0 eq) and XPhosPdG3 (16.0 mg, 0.02 mmol, 0.1 eq) in MeCN (1.8 mL) and water (0.2 mL) The mixture in was degassed with _N2 for 5 minutes, then heated to 60 °C and stirred for about 16 hours. The reaction was cooled to room temperature, then concentrated in vacuo. The crude product was purified by silica gel column chromatography (0% to 10% MeOH(NH3)/DCM) to give the title compound (23.2 mg, 26% yield) as a yellow gum. LCMS m/z: 378.4 [M+H] ⁺ , ESI pos.

The reaction was repeated again with 80 mg 5- bromine -N-[(3R)-1- Ethyl -3- piperidinyl ] zozolo [4,5-b] pyridine -2- Amines start.

step B : 2-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5- b ] pyridine -5- base ]-3- hydroxyl - Benzonitrile

BBr ₃ (0.95 mL, 0.95 mmol, 10 eq) was added dropwise to 2-[2-[[(3 R )-1-ethyl-3-piperidinyl]amino]oxazolo[ 4,5-b]pyridin-5-yl]-3-methoxy-benzonitrile (48.0 mg, 0.09 mmol, 1.0 eq) and tetrabutylammonium iodide (120.0 mg, 0.32 mmol, 3.5 eq) in DCM (3 mL), and the reaction was allowed to warm to room temperature. The reaction was further stirred for about 16 h, then quenched by dropwise addition to a stirred solution of _NH3 in MeOH (50 mL, 7M) at 0 °C. The solvent was concentrated in vacuo and the resulting residue was taken up in DCM (20 mL) and water (20 mL). The aqueous phase was adjusted to about pH 12 with NaOH (2M aq) and the organic phase was separated. The aqueous phase was then adjusted to about pH 7 with HCl (1M aq) and re-extracted with DCM (3 x 20 mL). The combined organic layers were dried over MgSO ₄ , concentrated in vacuo, and purified by silica gel column chromatography (12 g cartridge, 0% to 10% MeOH (0.7M NH ₃ )/DCM) to give an off-white solid The title compound (9.2 mg, 27% yield). LCMS m/z: 364.3 [M+H]+, ESI pos. Example 120 : 3- methyl -2-[2-[(2- methyl -2- azabicyclo [2.2.2] oct -4- yl ) amino ] oxazolo [4,5-b] pyridine -5- yl ]-5-( trifluoromethyl ) phenol

step A : 4-[(5- Chlorazolo [4,5- b ] pyridine -2- base ) Amino ]-2- Azabicyclo [2.2.2] Octane -2- Tertiary butyl formate

To a mixture of 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (150 mg, 0.748 mmol, 1.00 eq) in 1,4-dioxane (0.91 mL) successively Add tertiary-butyl 4-amino-2-azabicyclo[2.2.2]octane-2- carboxylate (186.11 mg, 0.822 mmol, 1.10 eq) and triethylamine (84.72 mg, 116.7 µL, 0.837 mmol, 1.12 eq). The brown solution was stirred overnight at 90 °C. Then, tertiary butyl 4-amino-2-azabicyclo[2.2.2]octane-2-carboxylate (64 mg, 0.234 mmol, 0.314 eq) and triethylamine (84.72 mg, 116.7 uL, 0.837 mmol, 1.120 eq) was added to the reaction mixture and stirring was continued at 100°C for 4 hours. The solvent was evaporated, and the residue was dissolved in NMP (0.91 mL). Triethylamine (84.7 mg, 117 µL, 0.837 mmol, 1.12 eq) was added to the reaction and it was stirred at 140 °C for two hours. Again, triethylamine (117 µL, 0.837 mmol, 1.12 eq) was added to the reaction mixture, and it was stirred at 140°C overnight. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate (about 20 mL) and 10% aqueous LiCl (about 5 mL). The aqueous layer was back extracted with ethyl acetate (about 20 mL). The organic layer was washed with water (about 10 mL) and brine (about 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 12 g, gradient: 0% to 10% MeOH in DCM) to afford the title compound (63 mg, 59%) as a white solid. LCMS m/z: 379.2 [M+H] ⁺ , ESI pos.

step B : 2- Azabicyclo [2.2.2] pungent -4- base -(5- Chlorazolo [4,5-b] pyridine -2- base ) amine

Following GP3 , the title compound was obtained as a white solid (30 mg, 53% yield). LCMS m/z: 279.1 [M+H] ⁺ , ESI pos.

step C : 5- Chlorazolo [4,5-b] pyridine -2- base )-(2- methyl -2- Azabicyclo [2.2.2] pungent -4- base ) amine

To 2-azabicyclo[2.2.2]oct-4-yl-(5-chloroazolo[4,5- b ]pyridin-2-yl)amine (30 mg, 0.11 mmol, 1.0 eq) in 1 , to a mixture in 2-dichloroethane (1.16 mL) was added triethylamine (16.77 mg, 23.1 µL, 0.166 mmol, 1.54 eq) and stirred at room temperature for 5 minutes. Then, 37% aqueous formaldehyde (11.6 mg, 10.66 µL, 0.143 mmol, 1.33 eq) and sodium triacetyloxyborohydride (68.6 mg, 0.324 mmol, 3.01 eq) were added sequentially, and stirring was continued at room temperature for 3 hours. Again, 37% aqueous formaldehyde (11.6 mg, 10.7 µL, 0.14 mmol, 1.3 eq) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with DCM (about 30 mL) and saturated aqueous NaHCO ₃ (about 5 mL). The aqueous layer was back extracted twice with DCM (about 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was subjected to flash chromatography (silica gel, 4 g, DCM/MeOH gradient: 0% to 20% methanol + 1% NH ₃ ) to afford the title compound (19 mg, 60%) as an off-white solid. LCMS m/z: 293.1 [M+H] ⁺ , ESI pos.

step D. : 3- methyl -2-[2-[(2- methyl -2- Azabicyclo [2.2.2] pungent -4- base ) Amino ] zozolo [4,5-b] pyridine -5- base ]-5-( Trifluoromethyl ) phenol

5- Chloroxazolo [4,5- b ]pyridin-2-yl)-(2-methyl-2-azabicyclo[2.2.2]oct-4-yl)amine (16 mg , 54.7 µmol, 1.0 eq) and 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-( Trifluoromethyl)phenol (24 mg, 19.8 µL, 79.4 µmol, 1.45 eq) was reacted to give the title compound (7.3 mg, 28% yield) as a yellow solid. LCMS m/z: 431.2 [MH] ^- , ESI neg. Example 121 : 5-( Difluoromethyl )-3- methyl -2-[2-[[(3 R )-1- methyl -3- piperidinyl ] amino ] oxazolo [4,5 -b] pyridin -5- yl ] phenol

Similar to GP2a , 5-bromo- N -[( 3R )-1-methyl-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine; 2,2,2- Trifluoroacetic acid ( Example 30 , Step H ) (143.7 mg, 0.34 mmol, 1.2 eq) and 5-(difluoromethyl)-3-methyl-2-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)phenol (80.0 mg, 0.28 mmol, 1.0 eq) was reacted. The crude product was purified by column chromatography (C ₁₈ , 0.1% TFA in water/MeCN) and purified by preparative HPLC (column: Waters Xbridge 150×25 mm×5 um; conditions: water (NH ₄ HCO ₃ )-MeCN; B at the start: 29; B at the end: 59; Gradient time (min): 9; 100 % B hold time (min): 2; Flow rate (ml/min): 25) Purify again, The title compound was obtained as a yellow solid (14.49 mg, 0.04 mmol, 13% yield). LCMS: m/z 389.3 [M+H]+, ESI pos. Example 122 : 5-( Difluoromethyl )-2-[2-[[(3 R )-1- ethyl - 3- piperidinyl ] amino ] oxazolo [4,5-b] pyridine- 5- yl ]-3- methyl - phenol; 2,2,2- trifluoroacetic acid

Following GP2a , 5-bromo- N -[( 3R )-1-ethyl-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine ( Example 21 , Step H ) ( 41.2 mg, 0.13 mmol, 1.2 eq) with 5-(difluoromethyl)-3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxolane Borane-2-yl)phenol (30.0 mg, 0.11 mmol, 1.0 eq) was reacted. The crude product was purified by reverse phase flash chromatography (0.1% TFA water/ACN conditions, 60 g C ₁₈ cartridge, detection at 220 nm and 254 nm) to give the title compound (4.38 mg, 0.01 mmol) as a yellow solid , yield 8%). LCMS: m/z 403.2 [M+H]+, ESI pos. Example 123 : 2-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridin -5- yl ]-3,5- Dimethyl - phenol

step A : 2- iodine -3,5- Dimethyl - phenol

To a mixture of _3,5 -dimethylphenol (5.0 g, 40.93 mmol, 1.0 eq, CAS: 108-68-9) in toluene (100 mL) was added NaH (3.27 g, 81.86 mmol, 2.0 eq, 60%), stirred for 30 minutes, then added I ₂ (8.31 g, 32.74 mmol, 0.8 eq) and stirred at 25°C for 15.5 hours. The mixture was poured into 1N HCl (200 mL) and extracted with ethyl acetate (60 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 10:1) to obtain the title compound (1.10 g, yield 11%) as a white solid. LCMS: m/z 246.9 [MH]-, ESI neg.

step B : 1- Benzyloxy -2- iodine -3,5- Dimethyl - benzene

To a solution of 2-iodo-3,5-dimethyl-phenol (1.1 g, 4.43 mmol, 1.0 eq) in DMF (20 mL) was added K ₂ CO ₃ (1.23 g, 8.87 mmol, 2.0 eq ), then bromotoluene (0.79 mL, 6.65 mmol, 1.5 eq) was added dropwise. The reaction mixture was stirred at 25 °C under nitrogen atmosphere for 2 hours. Then, the reaction was quenched with water (50 mL), extracted with EtOAc (100 mL x 3), washed with brine (20 mL). The organic layer was dried over _Na2SO4 , filtered, and _the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 5:1) to obtain the title compound (1.3 g, yield 87%) as a colorless oil. ¹ H NMR (400 MHz, CD ₃ OD) δ [ppm]: 7.52 (d, 2H), 7.39 - 7.35 (m, 2H), 7.32 - 7.25 (m, 1H), 6.76 (s, 1H), 6.62 ( s, 1H), 5.19 (s, 1H), 5.11 (s, 2H), 2.40 (s, 3H), 2.26 (s, 3H).

step C : 2-(2- Benzyloxy -4,6- Dimethyl - Phenyl )-4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane

Under nitrogen gas, 1-benzyloxy-2-iodo-3,5-dimethyl-benzene (650.0 mg, 1.92 mmol, 1.0 eq) and 2-isopropoxy-4,4,5,5 -Tetramethyl-1,3,2-dioxaborolane (643.71 mg, 3.46 mmol, 1.8 eq) in THF (7 mL) was added dropwise nBuLi (1.15 mL, 2.88 mmol, 1.5 eq), and stirred at -60°C for 30 minutes. The mixture was poured into aqueous NH ₄ Cl solution (30 mL), and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 20:1) to obtain the title compound (500.0 mg, 1.48 mmol, yield 77%) as a colorless oil. ¹ H NMR (400 MHz, CD ₃ OD) δ [ppm]: 7.47 (d, 2H), 7.37 - 7.28 (m, 3H), 6.62 (d, 2H), 4.99 (s, 2H), 2.28 (d, 6H), 1.27 (s, 12H).

step D. : (2- hydroxyl -4,6- Dimethyl - Phenyl ) boric acid and 3,5- Dimethyl -2-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base ) phenol

2-(2-Benzyloxy-4,6-dimethyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (250.0 mg , 0.74 mmol, 1.0 eq) in EtOAc (3 mL) was degassed and purged three times with H ₂ , then a batch of Pd/C (15 mg) and Pa(OH) ₂ (15.0 mg) was added to the in the mixture. The mixture was stirred at 25°C for 2 hours. The mixture was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (100.0 mg, 0.4 mmol, 55% yield) as a yellow oil. ¹ H NMR (400 MHz, CD ₃ OD) δ [ppm]: 6.49 (s, 1H), 6.43 (s, 1H), 4.87 (s, 7H), 2.38 (s, 3H), 2.21 (s, 3H) , 2.01 (s, 1H), 1.38 (s, 12H).

step E. : 2-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3,5- Dimethyl - phenol

CsF (104.08 mg, 0.75 mmol, 2.5 eq), (2-hydroxy-4,6-dimethyl-phenyl)boronic acid (50.0 mg, 0.3 mmol, 1.0 eq) and 5-bromo-N-[(3R )-1-ethyl-3-piperidinyl]oxazolo[4,5-b]-pyridin-2-amine (97.96 mg, 0.3 mmol, 1.0 eq) in 1,4-dioxane (1 mL ) and water (0.2 mL) was degassed and purged with N ₂ three times, and Pd(dppf)Cl 2 (22.04 mg, 0.03 mmol, 0.1 eq) was added to the mixture. The mixture was stirred at 90 °C for 2 hours under microwave irradiation. Then, the reaction mixture was poured into water (10 mL), and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the residue was subjected to C18 column chromatography (20 g, 0.1% TFA in water/MeCN) to give white The title compound as a solid (5.1 mg, 0.01 mmol, 5% yield). LCMS: m/z 367.2. [M+H]+, ESI pos. Example 124 : 3-[[5-(4- chloro -2- hydroxyl -6 - methyl - phenyl ) oxazolo [4,5- b ] pyridin -2- yl ] amino ]-1- ethyl -piperidin - 4- ol

step A : 3-[(5- Chlorazolo [4,5-b] pyridine -2- base ) Amino ]-1- Ethyl - piperidine -4- alcohol

5-Chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (300 mg, 1.4 mmol, 1.0 eq) in 1,4-dioxane (1.5 mL ) and NMP (1.5 mL) were added successively 3-amino-1-ethyl-piperidin-4-ol; hydrochloride (308 mg, 1.7 mmol, 1.2 eq) and triethylamine (359.3 mg, 495 µL, 3.55 mmol, 2.5 eq). The brown solution was stirred at 100°C for 16 hours, then heated to 150°C for 4 hours. To the stirred dark brown reaction mixture at room temperature was added more 3-amino-1-ethyl-piperidin-4-ol; hydrochloride (100 mg, 0.553 mmol, 0.4 eq) and triethylamine ( 72.6 mg, 100 µL, 0.72 mmol, 0.501 eq), and the mixture was heated to 150°C for 6 hours. The reaction mixture was quenched with water (10 mL) and extracted twice with ethyl acetate (2 x 30 mL). The organic layer was washed with water (30 mL) and brine (30 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered off and concentrated in vacuo. The crude product was subjected to flash chromatography (silica gel, 0% to 90% DCM:MeOH: _NH4OH (v/v) 110:10:1 in DCM) to give the title compound as a dark brown solid (80 mg, Yield 19%). LCMS m/z: 297.1 [M+H] ⁺ , ESI pos.

step B : 3-[[5-(4- chlorine -2- hydroxyl -6- methyl - Phenyl ) zozolo [4,5- b ] pyridine -2- base ] Amino ]-1- Ethyl - piperidine -4- alcohol

3-[(5-Chloroxazolo[4,5-b]pyridin-2 - yl)amino]-1-ethyl-piperidin-4-ol (80 mg, 0.27 mmol, 1.0 eq) was reacted with (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid (79.6 mg, 0.43 mmol, 1.6 eq) to give the title compound (20 mg, 19% yield) as a white solid. LCMS m/z: 401.2; 403.2 (Cl isotope) [MH]-, ESI neg. Example 125 : 2-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridin -5- yl ]-3- methyl -phenol _

According to GP2a , 5-chloro-N-[(3R)-1-ethyl-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine ( Example 14 , Step 1 ) (60 mg, 0.21 mmol, 1.0 eq) was reacted with (2-hydroxy-6-methyl-phenyl)boronic acid (52 mg, 0.34 mmol, 1.6 eq) to give the title compound (26 mg, Yield 35%). LCMS m/z: 353.2 [M+H] ⁺ , ESI pos. Example 126 : 5- fluoro -2-[2-[[(3 R )-1- methyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridin -5- yl ]- 3-( Trifluoromethyl ) phenol; 2,2,2- Trifluoroacetic acid

step A : 1-( Benzyloxy )-2- bromine -5- fluorine -3-( Trifluoromethyl ) benzene

To a solution of 2-bromo-5-fluoro-3-(trifluoromethyl)phenol (500.0 mg, 1.93 mmol, 1.0 eq) in DMF (5 mL) was added K ₂ CO ₃ (533.6 mg, 3.86 mmol, 2.0 eq), then BnBr (495.3 mg, 2.9 mmol, 1.5 eq) was added, and the reaction mixture was stirred at 25 °C under nitrogen atmosphere for 2 hours. Then, the reaction mixture was quenched with 1N aqueous HCl (20 mL), extracted with ethyl acetate (100 mL × 3), washed with brine (20 mL). The combined organic layers were dried over anhydrous _Na2SO4 , filtered and the filtrate was concentrated under reduced _pressure . The residue was purified by silica gel chromatography (petroleum ether) to give the title compound (550.0 mg, 72% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.56 - 7.50 (m, 1H), 7.48 - 7.44 (m, 2H), 7.42 - 7.40 (m, 2H), 7.38 - 7.36 (m, 2H), 5.30 (s, 2H).

step B : 2-(2-( Benzyloxy )-4- fluorine -6-( Trifluoromethyl ) Phenyl )4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane

To 1-benzyloxy-2-bromo-5-fluoro-3-(trifluoromethyl)benzene (300.0 mg, 0.86 mmol, 1.0 eq) and 2-isopropoxy-4,4, To a solution of 5,5-tetramethyl-1,3,2-dioxaborolane (319.76 mg, 1.72 mmol, 2.0 eq) in THF (5 mL) was added n -BuLi (0.62 mL, 1.55 mmol, 1.8 eq), the reaction mixture was then stirred at this temperature for 1 h under nitrogen atmosphere. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (30 mL), extracted with ethyl acetate (100 mL×3) and washed with brine (20 mL). The combined organic layers were dried over anhydrous _Na2SO4 , filtered and the filtrate was concentrated under reduced _pressure . The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=10:0 to 10:1) to give the title compound (60.0 mg, yield 18%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm] 7.44-7.36 (m, 5H), 6.95 (d, 1H), 6.78 (d, 1H), 5.04 (s, 2H), 1.28 (s, 12H) .

step C : 5- fluorine -2-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base )-3-( Trifluoromethyl ) phenol

To 2-(2-(benzyloxy)-4-fluoro-6-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane To a mixture of pentaborane (40.0 mg, 0.1 mmol, 1.0 eq) in ethyl acetate (2 mL) was added Pd/C (10.0 mg, 10%) and the reaction was heated under ₁₁₀₀ mmHg of H at room temperature Stir for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give the title compound (30.0 mg, 97% yield) as a yellow solid. LCMS: m/z 305.0 [MH]-, ESI neg.

step D. : 5- fluorine -2-[2-[[(3R)-1- methyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3-( Trifluoromethyl ) phenol; 2,2,2- Trifluoroacetate

Under nitrogen gas, to 5-bromo- N -[(3 R )-1-methyl-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine; 2,2,2 - Trifluoroacetic acid ( Example 30 , Step H ) (40.0 mg, 0.09 mmol, 1.0 eq), 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaboran-2-yl)-3-(trifluoromethyl)phenol (25.91 mg, 0.08 mmol, 0.9 eq) and K ₂ CO ₃ (38.95 mg, 0.28 mmol, 3.0 eq) in 1,4-di To a solution in diane (1 mL)/water (0.2 mL) was added Pd(dppf)Cl ₂ (6.88 mg, 0.01 mmol, 0.1 eq) and the reaction was stirred at 95°C for 2 hours. The mixture was cooled to 25 °C, filtered and the filtrate concentrated in vacuo to give the crude product, which was purified by column chromatography (C ₁₈ , 0.1% TFA in water/MeCN) to give a yellow solid The title compound (5.23 mg, 10% yield). LCMS: m/z 411.1 [M+H]+, ESI pos. Example 127 : 5- chloro -2-[6- chloro -2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridine -5 -yl ] phenol _

step A : 6- bromine -5- chlorine -3- Methoxypyridine -2- amine

The device was dried by heating with an air heater under vacuum. To a mixture of 6-bromo-3-methoxypyridin-2-amine (800.0 mg, 3.94 mmol, 1.0 eq) in acetic acid (8 mL) was added N -chlorosuccinimide (578.75 mg, 4.33 mmol, 1.1 eq), and the mixture was stirred at 25°C for 6 hours. The reaction mixture was quenched by water (10 mL), then extracted by EtOAc (30 mL × 3), the combined organic phases were washed with brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and The filtrate was concentrated under reduced pressure. The residue was purified by column (petroleum ether:ethyl acetate=20:1 to 10:1) to obtain the title compound (710 mg, yield 76%) as a yellow solid. LCMS: m/z 236.9 [M+H] ⁺ , ESI pos.

step B : 2-(6- Amino -3- chlorine -5- Methoxypyridine -2- base )-5- chlorophenol

The device was dried by heating with an air heater under vacuum. To 6-bromo-5-chloro-3-methoxypyridin-2-amine (700.0 mg, 2.95 mmol, 1.0 eq), 4-chloro-2-hydroxyphenylboronic acid (558.89 mg, 3.24 mmol, 1.1 eq) and K ₂ CO ₃ (813.54 mg, 5.9 mmol, 2.0 eq) To a mixture of 1,4-dioxane (10 mL) and water (2 mL) was added Pd(dppf)Cl ₂ (215.47 mg, 0.29 mmol , 0.1 eq). The mixture was evacuated and backfilled three times with nitrogen and stirred at 90°C for 2 hours. After cooling to ambient temperature, the reaction mixture was quenched by adding water (10 mL), then extracted with EtOAc (10 mL × 3), and the combined organic phases were washed with brine (20 mL × 2), washed over anhydrous sulfuric acid Dry over sodium, filter, and concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 5:1) to obtain the title compound (600.0 mg, yield 71%) as a yellow solid. LCMS: m/z 284.9 [M+H]+, ESI pos.

step C : 2- Amino -5- chlorine -6-(4- chlorine -2- Hydroxyphenyl ) pyridine -3- alcohol

The device was dried by heating with an air heater under vacuum. Under nitrogen, 2-(6-amino-3-chloro-5-methoxypyridin-2-yl)-5-chlorophenol (50.0 mg, 0.18 mmol, 1.0 eq) and BBr ₃ (439.31 mg, 1.75 mmol, 10.0 eq) to the mixture was added DCM (0.5 mL), stirred at -60°C for 10 minutes, then the mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with ice water (2 mL) and neutralized with NH ₃ ·H ₂ O. The crude product was purified by column chromatography (C ₁₈ , 0.1% NH3·H2O in water/MeCN) to afford the title compound (20.0 mg, 42% yield) as a yellow solid. LCMS: m/z 270.9 [M+H]+, ESI pos.

step D. : 5- chlorine -2-(6- chlorine -2- Mercaptozozolo [4,5-b] pyridine -5- base ) phenol

The device was dried by heating with an air heater under vacuum. To a mixture of 2-amino-5-chloro-6-(4-chloro-2-hydroxyphenyl)pyridin-3-ol (20.0 mg, 0.07 mmol, 1.0 eq) in DMF (3 mL) was added TCDI (19.7 mg, 0.11 mmol, 1.5 eq), and the mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched by water (10 mL), then extracted with EtOAc (10 mL×3), washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, The title compound was obtained as a yellow solid (20.0 mg, 87% yield). LCMS: m/z 312.9 [M+H] ⁺ , ESI pos.

step E. : 5- chlorine -2-(2,6- Dichlorozozolo [4,5-b] pyridine -5- base ) phenol

The device was dried by heating with an air heater under vacuum. To 5-chloro-2-(6-chloro-2-mercaptooxazolo[4,5-b]pyridin-5-yl)phenol (20.0 mg, 0.06 mmol, 1.0 eq) in oxalyl chloride (405.32 mg, 3.19 mmol, 50.0 eq) was added DMF (0.47 mg, 0.01 mmol, 0.1 eq), and the mixture was stirred at 50°C for 1 hour. After cooling to ambient temperature, the reaction mixture was quenched by adding ice-water (5 mL), then extracted with EtOAc (10 mL × 3), washed with brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered And the filtrate was concentrated under reduced pressure to give the title compound (20.0 mg, 0.06 mmol, 99% yield) as a yellow solid. LCMS: m/z 316.7 [M+H]+, ESI pos.

step f : 5- chlorine -2-[6- chlorine -2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ] phenol

The device was dried by heating with an air heater under vacuum. To a mixture of 5-chloro-2-(2,6-dichlorooxazolo[4,5-b]pyridin-5-yl)phenol (20.0 mg, 0.06 mmol, 1.0 eq) in DMF (0.5 mL) DIEA (16.35 mg, 0.13 mmol, 2.0 eq) was added to , and the mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched by water (5 mL), then extracted by EA (10 mL × 3), washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed concentrate. The crude product was subjected to preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 µm; condition: water (NH ₄ HCO ₃ )-CAN; B at the beginning: 41; B at the end: 71; gradient time (minutes ): 9; 100% B hold time (min): 2; flow rate (ml/min): 25) Purified again to give the title compound (4.49 mg, 0.01 mmol, 17% yield) as a white solid. LCMS: m/z 407.1 [M+H]+, ESI pos. Example 128 : 3,5- Dimethyl -2-[2-[[(3 R )-1- methyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridine -5 -yl ] phenol; 2,2,2- trifluoroacetic acid

According to GP2a , 3,5-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol ( Example 123 , Step D) (63.79 mg, 0.26 mmol, 2.0 eq) with 5-bromo- N -[(3 R )-1-methyl-3-piperidinyl]oxazolo[4,5-b]pyridine-2 -Amine (40.0 mg, 0.13 mmol, 1.0 eq) reaction. The crude product was purified by column chromatography (C ₁₈ , 0.1% TFA in water/MeCN) to afford the title compound (6.83 mg, 11% yield) as a yellow oil. LCMS: m/z 353.2. [M+H] ⁺ , ESI pos. Example 129 : 3- Chloro -2-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridin -5- yl ]- 5- fluoro - phenol; 2,2,2- trifluoroacetic acid

step A : 3- chlorine -5- fluorine -2- iodine - Phenol and 5- chlorine -3- fluorine -2- iodophen

The device was dried by heating with an air heater under vacuum. To a mixture of 3-chloro-5-fluorophenol (1.0 g, 6.82 mmol, 1.0 eq) in toluene (10 mL) was added NaH (0.55 g, 13.7 mmol, 2.0 eq, 60 mL) at 0 °C under _N2 . %), stirred for 30 minutes to obtain a yellow solution, then added iodine (1.73 g, 6.82 mmol, 1.0 eq) and stirred at 25°C for 15.5 hours to obtain a white mixture. The mixture was quenched by adding water (20 mL), extracted with EtOAc (30 mL × 3), washed with brine (40 mL × 2), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was brought under reduced pressure concentrate. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10/1 to 5/1) to obtain 3-chloro-5-fluoro-2-iodo-phenol and 5- A 2:1 mixture of chloro-3-fluoro-2-iodophenol (700 mg, 38% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.26 (br. s, 1H), 7.00 (d, 1H), 6.65 (d, 1H).

step B : 1- chlorine -5- fluorine -2- iodine -3- Methoxy - Benzene and 5- chlorine -1- fluorine -2- iodine -3- Methoxybenzene

The device was dried by heating with an air heater under vacuum. To a solution of 3-chloro-5-fluoro-2-iodo-phenol (700 mg, 2.57 mmol, 1.0 eq) in DMF (1 mL) was added _Cs2CO3 ( _1674.2 mg, 5.14 mmol, 2.0 eq), And the mixture was stirred at 25 °C for 5 minutes, then MeI (1094.6 mg, 7.71 mmol, 3.0 eq) was added to the mixture and stirring was continued for 2 hours. The reaction mixture was quenched by adding water (10 mL), extracted with EtOAc (20 mL × 3), washed with brine (30 mL × 2), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was decompressed Concentrate. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:0 to 10:1) to give 1-chloro-5-fluoro-2-iodo-3-methoxy as a yellow solid - 2:1 mixture of benzene and 5-chloro-1-fluoro-2-iodo-3-methoxybenzene (450 mg, 61% yield). ¹ H NMR (DMSO-d ₆ , 400 Hz) δ [ppm]: 7.20 (d, 1H), 6.96 (d, 1H), 3.87 (s, 3H).

step C : 2-(2- chlorine -4- fluorine -6- Methoxy - Phenyl )-4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane and 2-(4- chlorine -2- fluorine -6- Methoxyphenyl )-4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane

The device was dried by heating with an air heater under vacuum. 1-Chloro-5-fluoro-2-iodo-3-methoxy-benzene (200 mg, 0.7 mmol, 1.0 eq) and 2-isopropoxy-4,4,5,5- To a mixture of tetramethyl-1,3,2-dioxaborolane (194.9 mg, 1.05 mmol, 1.5 eq) in THF (3 mL) was added n -BuLi (0.42 mL, 0.84 mmol, 1.2 eq ), and the mixture was stirred at -10°C for 30 min to obtain a colorless solution. The reaction mixture was quenched by the addition of saturated aqueous _NH4Cl (5 mL), then diluted with water (5 mL). After extraction with EtOAc (30 mL x 3), the organic phase was washed with brine (40 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 5:1) to obtain 2-(2-chloro-4-fluoro-6-methoxy- Phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 2-(4-chloro-2-fluoro-6-methoxyphenyl)- 2:1 mixture of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (70.0 mg, 35% yield). ¹ H NMR (CD ₃ OD, 400 MHz) δ [ppm]: 6.74 (s, 1H), 6.71 (s, 1H), 3.76 (s, 3H), 1.30 (s, 12H).

step D. : (2- chlorine -4- fluorine -6- hydroxyl - Phenyl ) boric acid and (4- chlorine -2- fluorine -6- Hydroxyphenyl ) boric acid

The device was dried by heating with an air heater under vacuum. Under nitrogen gas, to 2-(2-chloro-4-fluoro-6-methoxy-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxolane To a mixture of borane (70.0 mg, 0.24 mmol, 1.0 eq) in DCM (0.5 mL) was added BBr ₃ (612.03 mg, 2.44 mmol, 10.0 eq) to give a white solution, and the mixture was stirred at -60 °C for 10 minutes, then stirred at 25°C for 1 hour. The reaction was quenched by the addition of ice water (2 mL) and neutralized by the addition of aqueous ammonia to give a yellow solution. After removal of the solvent, the solution was purified by reverse phase flash chromatography (0.1% NH ₃ ·H ₂ O water/ACN conditions) to afford (2-chloro-4-fluoro-6-hydroxy-phenyl) as a white solid 2:1 mixture of boronic acid and (4-chloro-2-fluoro-6-hydroxyphenyl)boronic acid (25.0 mg, 38% yield). LCMS: m/z 189.0 [MH] ^- , ESI neg.

step E. : ( R )-3- chlorine -2-(2-((1- Ethylpiperidine -3- base ) Amino ) zozolo [4,5-b] pyridine -5- base )-5- Fluorophenol 2,2,2- Trifluoroacetate and (R)-5- chlorine -2-(2-((1- Ethylpiperidine -3- base ) Amino ) zozolo [4,5-b] pyridine -5- base )-3- Fluorophenol 2,2,2- Trifluoroacetate

The device was dried by heating with an air heater under vacuum. To 5-bromo- N -[(3 R )-1-ethyl-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine; 2,2,2-trifluoroacetic acid ( Example 21 , Step H ) (32.3 mg, 0.07 mmol, 0.7 eq), (2-chloro-4-fluoro-6-hydroxy-phenyl)boronic acid and (4-chloro-2-fluoro-6-hydroxyphenyl) Boric acid (20.0 mg, 0.11 mmol, 1.0 eq 70%) and K ₂ CO ₃ (29.0 mg, 0.21 mmol, 2.0 eq) in a mixture of 1,4-dioxane (0.5 mL) and water (0.1 mL) Pd(dppf) _Cl2 (7.68 mg, 0.01 mmol, 0.1 eq) was added to give a red mixture, which was then stirred at 90°C under _N2 for 2 hours to give a brown solution. The reaction mixture was quenched by adding water (2 mL), then diluted with MeOH (2 mL) to give a brown solution. The solution was purified by reverse phase flash chromatography (C ₁₈ cartridge, 0.1% TFA water/ACN conditions) to afford 3-chloro-2-[2-[[(3 R )-1-ethane as a white solid Base-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-fluoro-phenol; 2,2,2-trifluoroacetic acid (2.51 mg, yield 4.7 %). LCMS: m/z 391.1 [M+H] ⁺ , ESI pos. ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.79 (d, 1H), 7.13 (d, 1H), 7.65 (d, 1H), 7.63 (d, 1H),4.20-4.14(m, 1H), 4.00 -3.95 (m, 1H), 3.68-3.55 (m, 1H), 3.26-3.24(m, 2H), 3.00-2.98 (m, 1H), 2.90-2.75 (m, 1H), 2.26-2.24 (m, 1H), 2.18-2.10 (m, 1H), 2.00-1.80 (m, 1H), 1.76-1.60 (m, 1H), 1.39-1.36 (m, 3H).

5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]- 3-fluoro-phenol; 2,2,2-trifluoroacetic acid (1.5 mg, 2.8% yield). LCMS: m/z 391.1 [M+H] ⁺ , ESI pos. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.6 (br. s, 0.45 H), 9.45 (br. s, 0.30 H), 9.03 (br. s, 0.38 H), 7.92 (d, 1H), 7.40 (d, 1H), 6.90 (d, 1H), 6.84 (s, 1H), 3.80-3.70 (m, 1H), 3.51-3.48 (m, 1H), 3.33-3.23(m, 2H), 3.00- 2.90 (m, 1H),2.88-2.68 (m, 1H), 2.18-2.10(m, 1H), 2.00-1.80 (m, 2H), 1.76-1.60 (m, 1H),1.58-1.50 (m, 1H ). 1.39-1.36 (m, 3H). Example 130 : 5-( Difluoromethoxy )-2-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridine -5- yl ]-3- methyl - phenol; 2,2,2- trifluoroacetic acid

step A : 3-( Difluoromethoxy )-5- Methylphenol

To a solution of 5-methylresorcinol (CAS # 504-15-4, 5.00 g, 40.3 mmol, 1.0 eq) in DMF (150 mL) and water (25 mL) at 25 °C was added _{Cs2CO 3} (2.62 g, 80.6 mmol, 2.0 eq) and sodium 2-chloro-2,2-difluoroacetate (CAS # 1895-39-2, 7417.6 mg, 48.3 mmol, 1.2 eq), after stirring for 15 minutes, the reaction The mixture was warmed to 100°C and stirred under nitrogen atmosphere for 4 hours. Subsequently, the reaction mixture was quenched with 1N HCl (pH about 5), extracted with EtOAc (100 mL × 3), washed with brine (20 mL × 2), dried over Na ₂ SO ₄ , filtered and the filtrate was decompressed Concentrate. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 6:1) to obtain the title compound (1.70 g, yield 24%) as yellow oil. ¹ H NMR (CDCl ₃ , 400 MHz,) δ [ppm]: 6.66 -6.29 (m, 4H), 4.79 (br s, 1H), 2.31 (s, 3H).

step B : 5-( Difluoromethoxy )-2- iodine -3- Methylphenol

To a solution of 3-(difluoromethoxy)-5-methyl-phenol (390 mg, 2.24 mmol, 1.0 eq) in toluene (4 mL) was added NaH (179.2 mg, 4.48 mmol, 2.0 eq 60% ). After stirring at 0 °C for 10 min, a solution of iodine (397.9 mg, 1.57 mmol, 0.7 eq) in toluene (4 mL) was added dropwise and the reaction mixture was stirred at 25 °C under nitrogen atmosphere for 12 h. Then, the reaction mixture was quenched with 1N HCl (pH about 4), extracted with EtOAc (100 mL × 3), washed with brine (20 mL × 2), the organic layer was dried over Na ₂ SO ₄ , filtered and the filtrate was Concentrate under reduced pressure. The crude product was purified by prep-TLC (petroleum ether:ethyl acetate=3:1, Rf=0.5) to give the title compound (250 mg, yield 37%) as yellow oil. LCMS: m/z 298.8 [MH] ^- , ESI neg.

step C : 1-( Benzyloxy )-5-( Difluoromethoxy )-2- iodine -3- Toluene

To a solution of 5-(difluoromethoxy)-2-iodo-3-methyl-phenol (250.0 mg, 0.83 mmol, 1.0 eq) in N,N -dimethylformamide (5 mL) K ₂ CO ₃ (230.3 mg, 1.67 mmol, 2.0 eq) was added, followed by bromotoluene (0.15 mL, 1.25 mmol, 1.5 eq) dropwise, and the reaction mixture was stirred at 25°C under nitrogen atmosphere for 2 hours. Then, the reaction mixture was quenched with saturated aqueous NH ₄ Cl (30 mL), extracted with EtOAc (100 mL×3), the organic layer was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:0 to 20:1) to obtain the title compound (300 mg, yield 92%) as a colorless oil.

step D. : 2-(2-( Benzyloxy )-4-( Difluoromethoxy )-6- Tolyl )-4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane

Add 1-benzyloxy-5-(difluoromethoxy)-2-iodo-3-methyl-benzene (230 mg, 0.59 mmol, 1.0 eq) and 2-isopropoxy-4 at -60°C ,4,5,5-Tetramethyl-1,3,2-dioxaborolane (219.4 mg, 1.18 mmol, 2.0 eq) was added dropwise to a solution of n -BuLi in THF (5 mL) (0.46 mL, 1.15 mmol, 1.95 eq), and stirring was continued for 1 h at -60 °C under nitrogen atmosphere. The reaction was quenched with saturated aqueous NH ₄ Cl (30 mL), extracted with EtOAc (100 mL×3), washed with brine (10 mL). The organic layer was dried over anhydrous _Na2SO4 , filtered and the filtrate was concentrated under reduced _pressure . The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 10:1) to obtain the title compound (240 mg, 0.62 mmol, yield 89%) as a yellow oil. ¹ H NMR (CDCl ₃ , 400 MHz,) δ [ppm]: 7.46 (d, 1H), 7.38 – 7.32 (m, 3H), 6.64-6.27 (m, 3H), 5.00(s, 2H), 2.37 ( s, 3H), 1.37 (s, 12H).

step E. : 5-( Difluoromethoxy )-3- methyl -2-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base ) phenol

2-[2-Benzyloxy-4-(difluoromethoxy)-6-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxa A solution of cyclopentaborane (160.0 mg, 0.41 mmol, 1.0 eq) in EtOAc (6 mL) and methanol (2 mL) was degassed and purged with nitrogen three times, then Pd/C (60 mg) was added, and The mixture was degassed and purged with hydrogen three times. The reaction mixture was stirred at 20 °C for 2 h under hydrogen gas (15 psi). Then, the reaction mixture was filtered, the solid was washed with MeOH (20 mL×2), and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 0:1) to obtain the title compound (120.0 mg, yield 90%) as yellow oil. LCMS: m/z 301.1 [M+H] ⁺ , ESI pos.

step f : 5-( Difluoromethoxy )-2-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- methyl - phenol; 2,2,2- Trifluoroacetate

5-bromo- N -[(3 R )-1-ethyl-3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine; 2,2,2-trifluoroacetic acid ( Example 21 , Step H ) (30.0 mg, 0.07 mmol, 1.0 eq), 5-(difluoromethoxy)-3-methyl-2-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)phenol (30.1 mg, 0.1 mmol, 1.47 eq) and K ₂ CO ₃ (47.14 mg, 0.34 mmol, 5.0 eq) in 1,4-dioxane ( 3 mL) and water (0.3 mL) were degassed and purged with nitrogen gas three times. Then Pd(dppf) _Cl2 (4.99 mg, 0.01 mmol, 0.1 eq) was added and the reaction mixture was degassed and purged with nitrogen three times. Then, the mixture was stirred at 100°C for 2 hours. After cooling to room temperature, the mixture was diluted with MeOH (20 mL) and EtOAc (20 mL), filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (0.1% TFA/MeCN conditions) to afford the title compound (19.3 mg, 53% yield) as a yellow solid. LCMS: m/z 419.2 [M+H] ⁺ , ESI pos. Example 131 : 2-[2-[(1- ethylpyrrolidin -3- yl ) amino ] oxazolo [4,5-b] pyridin -5- yl ]-3- methyl -5-( tri Fluoromethyl ) phenol

step A : 3-[(5- Chlorazolo [4,5- b ] pyridine -2- base ) Amino ] Pyrrolidine -1- Tertiary butyl formate

According to GP1 , 5-chloro-2-(methylthio)oxazolo[4,5- b ]pyridine (150 mg, 0.748 mmol, 1.0 eq) was mixed with 3-aminopyrrolidine-1-carboxylic acid tertiary butyl The ester (155 mg, 0.83 mmol, 1.1 eq) was reacted to give the title compound (265 mg, 94%) as a brown solid. LCMS m/z: 383.1 [M+H-tBu] ⁺ , ESI pos.

step B : (5- Chlorazolo [4,5- b ] pyridine -2- base )- Pyrrolidine -3- base - amine

3-[(5-Chloroxazolo[4,5-b]pyridin-2-yl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (262 mg, 0.7 mmol, 1.0 eq) was dissolved in MeOH (2.5 mL), and 4 M HCl in dioxane (1.57 mL, 6.26 mmol, 9.0 eq) was added dropwise to the reaction mixture and stirred at room temperature for 2 hours. The solvent was removed and the crude product was taken up in ethyl acetate (25 mL) and water (10 mL). The aqueous phase was back extracted twice with EtOAc (20 mL). LC-MS showed product in the aqueous layer. 1N NaOH (5 mL) (pH 10) was added to the aqueous layer. A light brown solid precipitated out. The aqueous phase was re-extracted with DCM (30 mL). The organic phases were combined and washed with brine (10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, DCM/MeOH (0% to 10% MeOH with 1% NH ₃ )) to afford the title compound (54 mg, 27% yield) as a brown solid. LCMS m/z: 239.1 [M+H] ⁺ , ESI pos.

step C : (5- Chlorazolo [4,5- b ] pyridine -2- base )-(1- Ethylpyrrolidine -3- base ) amine

According to GP4 , (5-Chloroxazolo[4,5- b ]pyridin-2-yl)-pyrrolidin-3-yl-amine; hydrochloride (50 mg, 0.15 mmol, 1.0 eq) was mixed with acetaldehyde (13.4 mg, 15.19 µL, 0.3 mmol, 2.0 eq) were reacted to afford the title compound (11 mg, 28% yield) as a pale yellow solid. LCMS m/z: 267.1 [M+H] ⁺ , ESI pos.

step D. : 2-[2-[(1- Ethylpyrrolidine -3- base ) Amino ] zozolo [4,5-b] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl ) phenol

(5- Chloroxazolo [4,5-b]pyridin-2-yl)-(1-ethylpyrrolidin-3-yl)amine (10 mg, 0.037 mmol, 1.0 eq) was mixed with [ 2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]boronic acid (12 mg, 0.054 mmol, 1.45 eq) was reacted to give the title compound (8.5 mg, 50%) as a yellow solid. LCMS m/z: 407.2 [M+H] ⁺ , ESI pos. Example 132 : 3,5 - Dichloro -2-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5-b] pyridine -5- base ] phenol; 2,2,2- trifluoroacetic acid

step A : 3,5- Dichloro -2- iodophen

Set up the 100 mL reactor under inert gas. Iodine (3.11 g, 12.3 mmol, 1.0 eq) was dissolved in toluene (10 mL) at 25 °C and stirred until completely dissolved (0.5 h), toluene (5 mL) was injected into the reactor, and NaH (982 mg, 24.5 mmol, 2.0 eq, 60%). The suspension was cooled to 0°C to 5°C and 3,5-dichlorophenol (2.0 g, 12.27 mmol, 1.0 eq) in toluene (8 mL) was added within 0.5 h maintaining the internal temperature < 10°C solution in. After the addition was complete, stirring was continued for 4 hours. The reaction was then quenched by the addition of 1N aqueous HCl (10 mL) while maintaining the internal temperature <15°C. The layers were separated, and the aqueous phase was extracted with EtOAc (100 mL). The combined _organic phases were washed with brine, dried over _Na2SO4 , filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1 to 10/1) to obtain the title compound (1.4 g, yield 39%) as a yellow solid. LCMS: m/z 286.7 [MH] ^- , ESI neg.

step B : 1,5- Dichloro -2- iodine -3- Methoxybenzene

Set up the 100 mL reactor under inert gas. Under nitrogen gas, 3,5-dichloro-2-iodo-phenol (1.4 g, 4.85 mmol, 1.0 eq) and Cs ₂ CO ₃ (2.37 g, 7.27 mmol, 1.5 eq) were dissolved in DMF (10 mL) was added dropwise MeI (1375.7 mg, 9.69 mmol, 2.0 eq) and the mixture was stirred at 50°C for 4 hours. The reaction was then quenched by the addition of 1N HCl (10 mL) maintaining the internal temperature <15°C. The layers were separated, and the aqueous phase was extracted with EtOAc (100 mL). _The combined organic layers were washed with brine, dried over _Na2SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1 to 10/1) to obtain the title compound (1.0 g, yield 68%) as a white solid. ¹ H NMR (CDCl ₃ , 400 MHz) δ [ppm]: 7.14 (s, 1H), 6.69 (s, 1H), 3.90 (s, 3H).

step C : 2-(2,4- Dichloro -6- Methoxyphenyl )-4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane

Under nitrogen gas, 1,5-dichloro-2-iodo-3-methoxy-benzene (500.0 mg, 1.65 mmol, 1.0 eq), 2-isopropoxy-4,4,5,5- To a mixture of tetramethyl-1,3,2-dioxaborolane (552.8 mg, 2.97 mmol, 1.8 eq) in anhydrous THF (10 mL) was added dropwise n BuLi (1.19 mL, 2.97 mmol, 1.8 eq), and stirred at -70°C for 30 minutes. The mixture was poured into saturated aqueous NH ₄ Cl solution (20 mL), and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1 to 20/1) to obtain the title compound (270.0 mg, yield 54%) as a white solid. ¹ H NMR (CD ₃ OD, 400 MHz) δ [ppm]: 6.98 (s, 1H), 6.92 (s, 1H), 3.79 (s, 3H), 1.36 (s, 12H).

step D. : (2,4- Dichloro -6- Hydroxyphenyl ) boric acid

Under nitrogen gas, 2-(2,4-dichloro-6-methoxy-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxo To a solution of borane (270 mg, 0.89 mmol, 1.0 eq) in DCM (2 mL) was added _BBr3 (2.30 g, 17.8 mmol, 20.0 eq) dropwise, and the mixture was stirred at 25 °C for 2 h . The reaction mixture was poured into 10 mL of water at 0 °C and the pH was adjusted to 8 by adding 1 N aqueous NaOH. The mixture was washed with DCM (10 mL x 3), then acidified with 1N aqueous HCl to pH = 4, and a white precipitate formed. Collected by filtration and air dried to give the title compound (0.8 g, 87% yield) as a white solid. LCMS: m/z 203.9, [MH] ^- , ESI neg.

step E. : 3,5- Dichloro -2-[2-[[(3R)-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ] phenol; 2,2,2- Trifluoroacetate

The device was dried by heating with an air heater under vacuum. (2,4-Dichloro-6-hydroxyphenyl)boronic acid (353.15 mg, 0.340 mmol, 3 eq), 5-bromo- N -[(3 R )-1-ethyl -3-piperidinyl]oxazolo[4,5-b]pyridin-2-amine; 2,2,2-trifluoroacetic acid ( Example 21 , Step H ) (50.0 mg, 0.110 mmol, 1 eq) and To a solution of K ₂ CO ₃ (78.55 mg, 0.570 mmol, 5 eq) in 1,4-dioxane (2 mL)/water (0.2 mL) was added Pd(dppf)Cl ₂ (8.32 mg, 0.010 mmol, 0.1 eq). The reaction mixture was stirred at 90 °C for 3 hours. After cooling to room temperature, EtOAc (40 mL) and water (40 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (50 mL x 5). The combined extracts were washed with brine (60 mL), dried over MgSO ₄ , filtered, and concentrated in vacuo. The crude product was purified by column chromatography (C ₁₈ , 0.1% TFA in water/MeCN) to afford the title compound (7.95 mg, 17% yield) as a yellow solid. LCMS: m/z 407.1, [M+H] ⁺ , ESI pos. Example 133 : 2-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ]-6- fluoro -1H- imidazo [4,5-b] pyridin -5- yl ]-5-( trifluoromethyl ) phenol

step A : 2,6- Dichloro -3- fluorine -5- Nitropyridine

To _H2SO4 solution (21.3 g, 216.9 mmol, 4.0 eq) was added 2,6 _- dichloro-3-fluoro-pyridine (CAS # 52208-50-1, 9.0 g, 54.2 mmol, 1.0 eq) at 0 °C ) to obtain a pale yellow solution. Then, fuming nitric acid (26.3 g, 271.1 mmol, 5.0 eq) was added to the mixture at 0°C to obtain a yellow solution, and the mixture was stirred at 0°C for 1 hour, and then the mixture was stirred at 100°C for 12 hours . The reaction mixture was quenched by 100 mL of ice water, then extracted with EtOAc (200 mL x 3), washed with brine (200 mL x 2), filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 10:1) to obtain the title compound (5.40 g, yield 47%) as a yellow solid. ¹ H NMR (DMSO-δ ₆ , 400 MHz) δ [ppm]: 8.97 (d, 1H).

step B : 2- chlorine -5- fluorine -6-(2- Methoxy -4-( Trifluoromethyl ) Phenyl )-3- Nitropyridine

2,6-dichloro-3-fluoro-5-nitro-pyridine (450 mg, 2.13 mmol, 1.0 eq), 2 _- methoxy-4-(trifluoromethyl )-phenylboronic acid (516.1 mg, 2.35 mmol, 1.1 eq; CAS: 312936-89-3), CsF (991.8 mg, 6.4 mmol, 3.0 eq) in 1,4-dioxane (5 mL)/water ( 1 mL) solution. The reaction mixture was stirred at 100°C for 3 hours. After cooling to room temperature, EtOAc (40 mL) and water (40 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (50 mL x 5). The combined extracts were washed with brine (60 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo. The crude product was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to afford the title compound (300 mg, 28% yield) as a yellow solid. ¹ H NMR (CD ₃ OD, 400 MHz) δ [ppm]: 8.50-8.47 (m, 1H), 7.66-7.47 (m, 1H), 7.44-7.29 (m, 2H), 3.92 (s, 3H).

step C : 5- fluorine -6-(2- Methoxy -4-( Trifluoromethyl ) Phenyl )-3- Nitropyridine -2- amine

2-Chloro-5-fluoro-6-[2-methoxy-4-(trifluoromethyl)phenyl]-3-nitro-pyridine (250.0 mg, 0.71 mmol, 1.0 eq) and NH ₃ / MeOH (2.04 mL, 14.26 mmol, 20.0 eq) was stirred at 75 °C for 12 hours. The reaction mixture was concentrated under vacuum to obtain a residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 10:1) to obtain the title compound (150.0 mg , 0.45 mmol, yield 58%). LCMS: m/z 331.8, [M+H] ⁺ , ESI pos.

step D. : 5- fluorine -6-(2- Methoxy -4-( Trifluoromethyl ) Phenyl ) pyridine -2,3- diamine

5-Fluoro-6-[2-methoxy-4-(trifluoromethyl)phenyl]-3 _- nitro-pyridin-2-amine (770 mg, 2.32 mmol, 1.0 eq ) in methanol (10 mL) was added Pd/C (50.0 mg, 10%). The suspension was degassed under vacuum and flushed with _H2 several times. The mixture was stirred at 20 °C for 2 h under a balloon of _H2 . The reaction mixture was filtered, and the filter cake was washed with MeOH (10 mL x 5). The combined filtrates were concentrated to dryness to afford the title compound (600.0 mg, 65% yield) as a yellow solid. LCMS: m/z 302.2, [M+H] ⁺ , ESI pos.

step E. : 6- fluorine -5-(2- Methoxy -4-( Trifluoromethyl ) Phenyl )-3H- imidazo [4,5-b] pyridine -2- alcohol

To 5-fluoro-6-[2-methoxy-4-(trifluoromethyl)phenyl]pyridine-2,3-diamine (600.0 mg, 1.99 mmol, 1.0 eq) in THF (20 mL) To a solution of CDI (580.8 mg, 3.59 mmol, 1.8 eq) was added, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 2:1) to obtain the title compound (500 mg, yield 75%) as a white solid. LCMS: m/z 328.1, [M+H] ⁺ , ESI pos.

step f : 2- chlorine -6- fluorine -5-(2- Methoxy -4-( Trifluoromethyl ) Phenyl )-3H- imidazo [4,5-b] pyridine

6-Fluoro-5-[2-methoxy-4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridin-2-ol (500 mg, 1.53 mmol, 1.0 eq) and _POCl3 (9.37 g, 61.12 mmol, 40.0 eq) was stirred at 110 °C for 2 hours. The reaction mixture was concentrated under vacuum to give a residue, which was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:0 to 2:1) to obtain the title compound (150 mg, yield 27%). LCMS: m/z 346.1 [M+H] ⁺ , ESI pos.

step G : N -[(3 R )-1- Ethyl -3- piperidinyl ]-6- fluorine -5-[2- Methoxy -4-( Trifluoromethyl ) Phenyl ]-3H- imidazo [4,5-b] pyridine -2- amine; 2,2,2- Trifluoroacetate

2-Chloro-6-fluoro-5-[2-methoxy-4-(trifluoromethyl)phenyl]-3 H -imidazo[4,5-b]pyridine (150.0 mg, 0.43 mmol, 1.0 eq) and (3 R )-1-ethylpiperidin-3-amine (556.38 mg, 4.34 mmol, 10.0 eq), DIEA (111.95 mg, 0.87 mmol, 2.0 eq) in NMP (3 mL) Stir at 130°C for 32 hours. After cooling to room temperature, the reaction mixture was directly concentrated under reduced pressure to give a residue, which was purified on an automated flash chromatography system (ACN-0.1% TFA) to give the title compound (85.0 mg, Yield 35%). LCMS: m/z 438.2 [M+H]+, ESI pos.

step h : 2-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ]-6- fluorine -1 H - imidazo [4,5-b] pyridine -5- base ]-5-( Trifluoromethyl ) phenol

Under N ₂ , at -60°C, N -[(3 R )-1-ethyl-3-piperidinyl]-6-fluoro-5-[2-methoxy-4-(trifluoromethyl )-phenyl] -3H -imidazo[4,5-b]pyridin-2-amine; 2,2,2-trifluoroacetic acid (85.0 mg, 0.15 mmol, 1.0 eq) in DCM (1 mL) To a solution of BBr ₃ (0.4 g, 3.08 mmol, 20 eq) was added dropwise, and then the mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with MeOH (20 mL) at -60 °C. Then, the mixture was quenched with aqueous ammonia (to pH ~8). The precipitate was filtered off, and the filtrate was concentrated in vacuo, and the residue was purified by reverse phase flash chromatography (ACN-0.1% NH ₃ ·H ₂ O) to obtain the title compound as a white solid (15.5 mg, yield twenty three%). LCMS: m/z 424.2, [M+H] ⁺ , ESI pos. Example 134 : ( 3S , 5R )-5-[[5-(4- chloro -2- hydroxyl -6- methyl - phenyl ) oxazolo [4,5-b] pyridin -2- yl ] Amino ]-1- ethyl - piperidin -3- ol

The title compound was obtained as an off-white amorphous lyophilized solid from ( 3S , 5R )-5 - [(5-chlorooxazolo[4, 5- b ]pyridin-2-yl)amino]-1-ethyl-piperidin-3-ol ( Example 28 , step 3 ) and (4-chloro-2-hydroxyl-6-methyl-phenyl) Boronic acid ( CAS# 1207961-50-9 ) was prepared initially. LCMS: m/z 401.1; 403.1 (Cl isotope) [MH]-, ESI neg. Example 135 : 3- Methyl -2-[2-[4-( methylamino ) tetrahydropyran -4- yl ] oxazolo [4,5-b] pyridin -5- yl ]-5- ( Trifluoromethyl ) phenol; 2,2,2- Trifluoroacetic acid

step A : (4-((6- bromine -3- Hydroxypyridine -2- base ) carbamoyl ) Tetrahydro -2H- pyran -4- base ) Tertiary butyl carbamate

To DIEA (1.05 g, 8.15 mmol, 2.0 eq), 4-(( tertiary -butoxycarbonyl)amino)tetrahydro- 2H -pyran-4-carboxylic acid (1.00 g, 4.08 mmol, 1.0 eq) , HOBt (825.6 mg, 6.12 mmol, 1.5 eq) and EDCI (1.22 g, 6.12 mmol, 1.5 eq) in DMF (10 mL) were added 2-amino-6-bromopyridin-3-ol (770.6 mg, 4.08 mmol, 1.0 eq). The mixture was stirred at 25°C for 12 hours. The mixture was quenched with ice water (20 mL), and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with brine (40 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1 to 2:1) to obtain the title compound (800 mg, yield 47%) as a pink solid. LCMS: m/z 418.0, [M+2+H] ⁺ (Br isotope), ESI pos.

step B : (4-(5- bromozolo [4,5-b] pyridine -2- base ) Tetrahydro -2H- pyran -4- base ) Tertiary butyl carbamate

To a solution of DIAD (194.3 mg, 0.96 mmol, 2.0 eq) and PPh ₃ (252 mg, 0.96 mmol, 2.0 eq) in THF (3 mL) was added (4-((6-bromo-3-hydroxypyridine- 2-yl)carbamoyl)tetrahydro-2H-pyran-4-yl)tert- butylcarbamate (200.0 mg, 0.48 mmol, 1.0 eq), and the reaction mixture was stirred at 90°C for 12 hours. After cooling to ambient temperature, the reaction mixture was quenched by adding water (10 mL), extracted with ethyl acetate (20 mL × 3), washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered And the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (C18, 0.1% TFA in water-MeCN) to afford the title compound (60.0 mg, 31% yield) as a pink solid. LCMS: m/z 400.0, [M+2+H] ⁺ (Br isotope), ESI pos.

step C : (4-(5- bromozolo [4,5-b] pyridine -2- base ) Tetrahydro -2H- pyran -4- base )( methyl ) Tertiary butyl carbamate

The device was dried by heating with an air heater under vacuum. (4-(5-Bromozozolo[4,5-b]pyridin-2-yl)tetrahydro-2H-pyran-4-yl)carbamate tertiary butyl ester (150.0 mg, 0.38 mmol, 1.0 eq) To a mixture in THF (3 mL) was added t -BuOK/THF (0.56 mL, 0.56 mmol, 1.5 eq) followed by MeI (53.1 mg, 0.38 mmol, 1.0 eq). The mixture was stirred at 25 °C for 12 hours, then concentrated under reduced pressure to give the title compound (100.0 mg, 0.24 mmol, 64% yield) as a yellow oil. LCMS: m/z 414.0, [M+2+H] ⁺ (Br isotope), ESI pos.

step D. : 4-(5- bromozolo [4,5-b] pyridine -2- base )- N- Methyltetrahydro -2H- pyran -4- amine

The device was dried by heating with an air heater under vacuum. To (4-(5-bromoazolo[4,5-b]pyridin-2-yl)tetrahydro-2 H -pyran-4-yl)(methyl)carbamate tertiary butyl ester at 0°C (80.0 mg, 0.19 mmol, 1.0 eq) To a mixture in DCM (1 mL) was added TFA (44.24 mg, 0.39 mmol, 2.0 eq). The mixture was stirred at 25 °C for 2 hours, then concentrated under reduced pressure to give the title compound (80.0 mg, 97% yield) as a yellow solid. LCMS: m/z 312.0 [M+H] ⁺ , ESI pos.

step E. : 3- methyl -2-[2-[4-( Methylamino ) Tetrahydropyran -4- base ] zozolo [4,5-b] pyridine -5- base ]-5-( Trifluoromethyl ) phenol; 2,2,2- Trifluoroacetate

The device was dried by heating with an air heater under vacuum. To 4-(5-bromozozolo[4,5-b]pyridin-2-yl)-N-methyltetrahydro-2H-pyran-4-amine; 2,2,2 trifluoroacetic acid (70.0 mg, 0.16 mmol, 1.0 eq), [2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]boronic acid (54.19 mg, 0.25 mmol, 1.5 eq) in 1,4-dioxane ( 2 mL) and water (0.4 mL) were added K ₂ CO ₃ (68.0 mg, 0.49 mmol, 3.0 eq), then Pd(dppf)Cl ₂ (18.0 mg, 0.02 mmol, 0.15 eq) was added at 25°C Add to mixture. The mixture was stirred at 90 °C for 2 hours under nitrogen atmosphere. After cooling to ambient temperature, the reaction mixture was diluted with MeOH (5 mL) and purified by C18 column chromatography (0.1% TFA water-MeCN), followed by preparative HPLC (column: Phenomenex luna C ₁₈ 150 × 25 mm × 10 µm; Conditions: Water (TFA)-CAN; B at start: 25; B at end: 55; Gradient time (min): 11; 100% B hold time (min): 2; Flow rate (ml /min): 25) Purified again to afford the title compound (4.86 mg, 6% yield) as a white solid. LCMS: m/z 408.1 [M+H] ⁺ , ESI pos. Example 136 : 5- Chloro -2-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] -3H - imidazo [4,5-b] pyridine -5- base ]-3- methyl - phenol

step A : (5- bromine -1 H - imidazo [4,5- b ] pyridine -2- base )-[(3 R )-1- Ethyl -3- piperidinyl ] amine

To [(3 R )-1-ethyl-3-piperidinyl]amine; dihydrochloride (259.6 mg, 1.29 mmol, 3.0 eq) in N -methyl-2-pyrrolidinone (1 mL) To the mixture was added N,N -diisopropylethylamine (500.36 mg, 676 µL, 3.87 mmol, 9.0 eq). After stirring at ambient temperature for 10 minutes, 5-bromo-2-chloro-1H-imidazo[4,5-b]pyridine (CAS # 1260669-88-2, 100 mg, 0.430 mmol, 1.0 eq) was added. The reaction mixture was stirred at 120 °C in an oil bath for 16 hours. Then, more [( 3R )-1-ethyl-3-piperidinyl]amine; dihydrochloride (259.6 mg, 1.29 mmol, 3.0 eq) was added and stirring was continued at 150 °C for 24 hours. The reaction mixture was quenched with water (1 mL) and extracted with TBME (2 x 30 mL). The organic layer was washed with water (30 mL) and brine (30 mL). The combined organic extracts were dried over sodium sulfate, filtered off and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 80% DCM/MeOH/ _NH4OH 110:10:1 in DCM) to give the title compound (96 mg, 63%) as a light brown foam . LCMS: m/z 324.1; 326.1 (Br isotope) [M+H] ⁺ , ESI pos.

step B : 5- chlorine -2-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ]-3 H- imidazo [4,5-b] pyridine -5- base ]-3- methyl - phenol

The title compound was obtained as a light brown foam (48 mg, 40%), which was obtained from (5-bromo- 1H -imidazo[4,5- b ] using chemistry similar to that described in Example 18 (Step 3). Pyridin-2-yl)-[(3 R )-1-ethyl-3-piperidinyl]amine and (4-chloro-2-hydroxy-6-methyl-phenyl)boronic acid ( CAS # 1207961-50 -9 ) Start preparation. LCMS: m/z 386.2; 388.3 (Cl isotope) [M+H] ⁺ , ESI pos. Example 137 : 2-[2-[[(3 R )-1- ethyl -3- piperidinyl ] amino ] oxazolo [4,5- b ] pyridin -5- yl ]-3- methyl -5-( trifluoromethoxy ) phenol; 2,2,2- trifluoroacetic acid

step A : 3- methyl -5-( Trifluoromethoxy ) aniline

3-Bromo-5-(trifluoromethoxy)aniline (6.8 g, 26.56 mmol, 1.0 eq), trimethylboroxane terpolymer (11.38 mL, 39.84 mmol, 1.5 eq) and K ₂ CO ₃ (7.33 g, 53.12 mmol, 2.0 eq) in 1,4-dioxane (400mL) and water (80 mL) were degassed and purged with nitrogen three times, then Pd(dppf)Cl ₂ (0.97 g , 1.33 mmol, 0.05 eq) was added to the mixture. The mixture was stirred at 100°C for 12 hours. Then, the mixture was poured into water (200 mL), and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1 to 5/1) to afford the title compound (5.0 g, 98% yield) as a yellow oil. ¹ H NMR (CDCl ₃ , 400 MHz) δ [ppm]: 6.42 (s, 1H), 6.41 (s, 1H), 6.34 (s, 1H), 2.26 (s, 3H).

step B : 3- methyl -5-( Trifluoromethoxy ) phenol

To a mixture of 3-methyl-5-(trifluoromethoxy)aniline (5.0 g, 26.2 mmol, 1.0 eq) in H ₂ SO ₄ (10 mL)/water (10 mL) was added NaNO ₂ (3.61 g, 52.3 mmol, 2.0 eq), and purged with nitrogen three times. The mixture was stirred at 80°C for 3 hours. Then, the mixture was poured into water (200 mL), and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1 to 5 /1) Purification to give the title compound (1.4 g, 23% yield) as a yellow oil. ¹ H NMR (CDCl ₃ , 400 MHz) δ [ppm]: 6.62 (s, 1H), 6.58 (s, 1H), 6.53 (s, 1H), 2.32 (s, 3H). LCMS: m/z 191.0, [MH] ^- , ESI neg.

step C : 2,6- Diiodine -3- methyl -5-( Trifluoromethoxy ) phenol

To a mixture of 3-methyl-5-(trifluoromethoxy)phenol (1.40 g, 7.29 mmol, 1.00 eq) in toluene (20 mL) was added NaH (583 mg, 14.6 mmol, 2.0 eq, 60%), stirred for 30 minutes, then added iodine (1849.4 mg, 7.29 mmol, 1.0 eq), and stirred at 25°C for 15.5 hours. The mixture was poured into 1N aqueous HCl (50 mL), and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=100:1 to 10/1) to obtain the title compound (2.0 g, yield 62%) as a colorless oil. LCMS: m/z 442.8, [MH] ^- , ESI neg.

step D. : 2- iodine -3- methyl -5-( Trifluoromethoxy ) phenol

To a solution of benzyl N -[( 3R )-1-ethyl-3-piperidinyl]carbamate (10.0 g, 38.12 mmol, 1 eq) in methanol (100 mL) was added under nitrogen atmosphere Pd/C (100 mg, 10%). The suspension was degassed under vacuum and flushed with _H2 several times. The mixture was stirred at 20 °C for 2 h under a balloon of _H2 . The suspension was filtered, and the filter cake was washed with MeOH (100 mL x 5). The combined filtrates were concentrated to dryness to afford the title compound (1400.0 mg, 31% yield) as a white solid. LCMS: m/z 316.9, [MH] ^- , ESI neg.

step E. : 1-( Benzyloxy )-2- iodine -3- methyl -5-( Trifluoromethoxy ) benzene

Under nitrogen, 2-iodo-3-methyl-5-(trifluoromethoxy)phenol (1.4 g, 1.36 mmol, 1.0 eq), K ₂ CO ₃ (376.6 mg, 2.73 mmol, 2.0 eq) in To a solution in DMF (20 mL) was added BnBr (350.11 mg, 2.05 mmol, 1.5 eq). The mixture was then stirred at 25°C for 2 hours. The reaction was quenched by the addition of 1N HCl (10 mL) maintaining the internal temperature <15°C. The layers were separated, and the aqueous phase was extracted with EtOAc (100 mL). _The combined organic layers were washed with brine, dried over _Na2SO4 and filtered. The filtrate was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1 to 10/1) to obtain the title compound as a white solid (300 mg, yield 54 %). ¹ H NMR (CD ₃ OD, 400 MHz) δ [ppm]: 7.53-7.51 (m, 2H), 7.37-7.32(m, 3H), 6.71 (s, 1H), 6.68 (s, 1H), 5.17 ( s, 2H), 2.49 (s, 3H).

step f : 2-(2-( Benzyloxy )-6- methyl -4-( Trifluoromethoxy ) Phenyl )-4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane

Under nitrogen, add nBuLi (0.53 mL, 1.32 mmol, 1.8 eq) and 1-benzyloxy-2-iodo-3-methyl-5-(trifluoromethoxy)benzene (300.0 mg, 0.74 mmol, 1.0 eq) To a mixture in THF (10 mL) was added dropwise 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (205.14 mg, 1.1 mmol, 1.5 eq), and continued stirring at -70°C for 30 minutes. The mixture was poured into saturated aqueous NH ₄ Cl solution (20 mL), and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1 to 10/1) to obtain the title compound (110.0 mg, yield 37%) as a white solid. ¹ H NMR (CD ₃ OD, 400 MHz) δ [ppm]: 7.48-7.46 (m, 2H), 7.37-7.32(m, 3H), 6.88 (s, 1H), 6.74 (s, 1H), 5.02( s, 2H), 2.34 (s, 3H), 1.27 (s, 12H).

step G : 3- methyl -2-(4,4,5,5- Tetramethyl -1,3,2- Dioxaborolane -2- base )-5( Trifluoromethoxy ) phenol

Under nitrogen, to 2-[2-benzyloxy-6-methyl-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2- To a solution of dioxaborolane (100 mg, 0.24 mmol, 1.0 eq) in EtOAc (2 mL)/methanol (2 mL) was added Pd/C (10.0 mg, 10%). The suspension was degassed under vacuum and flushed with _H2 several times. The mixture was stirred at 20 °C under _H2 gas for 2 h. The suspension was filtered, and the filter cake was washed with MeOH (10 mL x 5). The combined filtrates were concentrated to dryness to give the title compound (60.0 mg, 0.19 mmol, 77% yield) as a yellow oil. ¹ H NMR (CD ₃ OD, 400 MHz) δ [ppm]: 6.54 (s, 1H), 6.48 (s, 1H), 2.43 (s, 3H), 1.38 (s, 12H).

step h : 2-[2-[[(3 R )-1- Ethyl -3- piperidinyl ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- methyl -5-( Trifluoromethoxy ) phenol; 2,2,2- Trifluoroacetate

Under nitrogen gas, 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoro Methoxy)phenol (20.0 mg, 0.06 mmol, 1.0 eq), 5-bromo-N-[(3R)-1-ethyl-3-piperidinyl]oxazolo[4,5-b]pyridine- 2-amine; 2,2,2-trifluoroacetic acid ( Example 21 , step H ) (33.1 mg, 0.08 mmol, 1.2 eq) and K ₂ CO ₃ (34.7 mg, 0.25 mmol, 4.0 eq) in 1,4- To a mixture in dioxane (1 mL)/water (0.2 mL) was added Pd(dppf)Cl ₂ (2.3 mg, 0.0 mmol, 0.05 eq) and stirring was continued at 95°C for 2 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (C ₁₈ , 0.1% TFA in water/MeCN) to afford the title compound (12.3 mg, 35% yield) as a yellow solid. LCMS: m/z 437.1, [M+H] ⁺ , ESI pos. Example 138 : 2-[2-(1- ethyl -3- piperidinyl ) oxazolo [4,5- b ] pyridin -5- yl ]-3- methyl -5-( trifluoromethyl ) phenol

step A : 5- bromine -2-(1- Ethylpiperidine -3- base ) zozolo [4,5-b] pyridine

2-Amino-6-bromopyridin-3-ol (100 mg, 0.53 mmol, 1.0 eq) and 1-ethylpiperidine-3-carboxylic acid (83.2 mg, 0.53 mmol, 1.0 eq) in PPA (1.0 mL ) was stirred at 150°C for 4 hours. After cooling to ambient temperature, the reaction mixture was diluted with ice-water (150 mL), then treated with saturated sodium carbonate to adjust the pH to about 10, and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was analyzed by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm; condition: water (ammonium hydroxide v/v)-ACN; B at the beginning: 5; B at the end: 35; gradient time (min): 9; 100% B hold time (min): 2; flow rate (ml/min): 25) Purification to afford the title compound (10 mg, 5% yield) as a yellow solid. LCMS: m/z 312.0 [M+2+H] ⁺ (Br isotope), ESI pos.

step B : 2-[2-(1- Ethyl -3- piperidinyl ) zozolo [4,5-b] pyridine -5- base ]-3- methyl -5-( Trifluoromethyl )- phenol

To 5-bromo-2-(1-ethylpiperidin-3-yl)oxazolo[4,5-b]pyridine (10.0 mg, 0.03 mmol, 1.0 eq) in 1,4-dioxane (1 mL) and water (0.2 mL) were added (2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boronic acid (14.2 mg, 0.06 mmol, 2.0 eq), Na ₂ CO ₃ (10.3 mg, 0.1 mmol, 3.0 eq) and Pd(dppf)Cl ₂ (4.72 mg, 0.01 mmol, 0.2 eq). The above reaction mixture was stirred at 100 °C for 2 hours under nitrogen atmosphere. After cooling to ambient temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (C ₁₈ , 0.1% NH ₃ ·H ₂ O in water-MeCN) to afford the title compound (7.97 mg, 60% yield) as a yellow oil. LCMS: m/z 406.0 [M+H] ⁺ , ESI pos. Examples 139a and 139b : 4-[2-[[( 8S , 8aS )-1,2,3,5,6,7,8,8a- swainson -8- yl ] amino ] oxazole And [4,5- b ] pyridin -5- yl ]-3- hydroxy- 5- methyl - benzonitrile or 4-[2-[[(8 R ,8a R )-1,2,3,5, 6,7,8,8a -Swainson -8- yl ] amino ] oxazolo [4,5- b ] pyridin -5- yl ]-3- hydroxy -5- methyl - benzonitrile and 4 -[2-[[(8 R ,8a R )-1,2,3,5,6,7,8,8a- swainson -8- yl ] amino ] oxazolo [4,5- b ] pyridin -5- yl ]-3- hydroxy -5 - methyl - benzonitrile or 4-[2-[[( 8S , 8aS )-1,2,3,5,6,7,8, 8a- Swainson- 8- yl ] amino ] oxazolo [4,5- b ] pyridin -5- yl ]-3- hydroxy -5- methyl - benzonitrile

step A : N -[ rel -(8R,8aR)-1,2,3,5,6,7,8,8a- Swainsonine -8- base ]-5- bromine - zozolo [4,5-b] pyridine -2- amine

To commercially available rel -(8 R ,8a R )-1,2,3,5,6,7,8,8a-swainsonin-8-amine; dihydrochloride (603 mg, 2.83 mmol, 1.1 eq), DIEA (1.66 g, 12.9 mmol, 5.0 eq) in DMF (10 mL) was added 5-bromo-2-chloro-oxazolo[4,5- b ]pyridine (600 mg , 2.57 mmol, 1.0 eq), and stirred at 25°C for 2 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to afford the title compound (700 mg, 81% yield) as a yellow solid. LCMS: m/z 339.1, [M+H] ⁺ ESI pos.

step B : 3- hydroxyl -5- methyl -4-[2-[[ rel -(8 R ,8a R )-1,2,3,5,6,7,8,8a- Swainsonine -8- base ] Amino ] zozolo [4,5-b] pyridine -5- base ] Benzonitrile

To (4-cyano-2-hydroxy-6-methyl-phenyl)boronic acid ( Example 25 , Step D ) (661.3 mg, 3.74 mmol, 1.8 eq), CsF (1.26 g, 8.3 mmol, 4.0 eq), N -[ rel -(8 R ,8a R )-1,2,3,5,6,7,8,8a-swainson-8-yl]-5-bromo-oxazolo[4,5 -b ] Pyridin-2-amine (700 mg, 2.08 mmol, 1.0 eq) To a mixture in 1,4-dioxane (20 mL)/water (4 mL) was added XPhos Pd G3 (175.9 mg, 0.21 mmol , 0.1 eq), and stirred at 95°C for 2 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase flash chromatography (water (0.1% TFA)-MeCN) to afford the title compound (400 mg, 49% yield) as a yellow solid. LCMS: m/z 390.2 [M+H] ⁺ ESI pos.

step C : 4-[2-[[(8 S ,8a S )-1,2,3,5,6,7,8,8a- Swainsonine -8- base ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- hydroxyl -5- methyl - Benzonitrile or 4-[2-[[(8 R ,8a R )-1,2,3,5,6,7,8,8a- Swainsonine -8- base ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- hydroxyl -5- methyl - Benzonitrile and 4-[2-[[(8 R ,8a R )-1,2,3,5,6,7,8,8a- Swainsonine -8- base ] Amino ] zozolo [4,5-b] pyridine -5- base ]-3- hydroxyl -5- methyl - Benzonitrile or 4-[2-[[(8 S ,8a S )-1,2,3,5,6,7,8,8a- Swainsonine -8- base ] Amino ] zozolo -[4,5-b] pyridine -5- base ]-3- hydroxyl -5- methyl - Benzonitrile

The above 3-hydroxy-5-methyl-4-[2-[[ rel- (8 R ,8a R )-1,2,3,5,6,7,8,8a-octahydro Indolazin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]benzonitrile (400 mg, 1.03 mmol, 1.0 eq) After chiral separation, the title compound was obtained (instrument: ACSWH - PREP-SFC-C, method column: DAICEL CHIRALPAK IC (250 mm × 30 mm × 10 µm)). White solid-like enantiomer 1 ( 139a ): (111.4 mg, yield 28%), ¹ H NMR (CD ₃ OD, 400 MHz) δ [ppm]: 7.66 (d, 1H), 7.13 (s, 1H ), 7.03 (s, 1H), 6.99 (d, 1H), 3.77 - 3.67 (m, 1H), 3.15 - 3.05 (m, 2H), 2.32 - 2.18 (m, 2H), 2.14 - 2.12 (m, 3H ), 2.10-2.09 (m, 1H), 2.08 - 2.02 (m, 2H), 1.86 - 1.66 (m, 5H), 1.45 - 1.31 (m, 1H). LCMS: m/z 390.4, (M+H) ⁺ (ESI+); and Enantiomer 2 ( 139b ) (112.3 mg, 28% yield) as a white solid. ¹ H NMR (CD ₃ OD, 400 MHz) δ [ppm]: 7.67 (d, 1H), 7.13 (s, 1H), 7.03 (s, 1H), 6.98 (d, 1H), 3.77 - 3.67 (m, 1H), 3.15 - 3.05 (m, 2H), 2.32 - 2.18 (m, 2H), 2.14 - 2.12 (m, 3H), 2.10-2.09 (m, 1H), 2.08 - 2.02 (m, 2H), 1.86 - 1.66 (m, 5H), 1.45 - 1.31 (m, 1H). LCMS: m/z 390.3 [M+H] ⁺ ESI pos. Example A

The compound of formula I can be used as such in a known manner as active ingredient for the manufacture of lozenges of the following compositions: per lozenge active ingredient 200mg microcrystalline cellulose 155mg corn starch 25mg talc 25mg Hydroxypropylmethylcellulose 20mg 425mg Example B

The compound of formula I can itself be used in a known manner as an active ingredient for the manufacture of capsules of the following composition: per capsule active ingredient 100.0mg corn starch 20.0mg lactose 95.0mg talc 4.5mg Magnesium stearate 0.5mg 220.0mg

Claims (41)

A compound of formula Ic, Ic wherein A ¹ is -N- or -CR ¹⁰ -; A ² is -O-, -NH-, -NCH ₃ - or -S-; R ¹ is H, halo, alkyl, haloalkyl, halo Alkoxy, cyano, alkoxy, cycloalkyl or alkylsulfonyl; R ⁹ is H, alkyl, halo or cyano; or R ¹ and R ⁹ form a 4-membered to 6-membered cycloalkyl group or a heterocycle containing a single O heteroatom; R ^is H, halo, alkyl, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxyalkyl, or hydroxyalkyl and ^R is H, halo or alkyl, wherein at least one of ^R2 and ^R3 is not H; ^R8 is H or halo; ^R10 is selected from H, alkyl, acetyl, alkylamino, Dialkylamino, hydroxyalkyl, hydroxyalkylalkyl, cyano, halo, haloalkyl, alkoxy, haloalkoxy and NR'R'', where R' and R'' are independently Selected from H and alkyl, or R' and R'' form a 4-membered to 6-membered N-containing heterocyclic ring or a 5-membered lactamide ring optionally substituted by -OH with the N atoms attached to them; n can be is 0 or 1; R ^X is H, alkyl, alkoxyalkyl or hydroxyalkyl; W is selected from 4 to 10 membered heterocycles containing up to 3 heteroatoms independently selected from N and O, Among them, the maximum number of O heteroatoms is 1, depending on the situation, 1 or 2 are selected from pendant oxy, -OH, halo, alkyl, alkoxyalkyl, alkylamino, dialkylaminoalkane hydroxyalkyl, cyano, haloalkyl, alkylester, alkylsulfon, cycloalkyl, heterocycle containing a single O heteroatom, cycloalkyl substituted with -OH, substituted with -OH Substituents of cycloalkyl-CH ₂ -, 6-membered heteroaryl substituted by alkoxy and 5-membered heteroaryl having 2 N heteroatoms, containing up to 2 independently selected from N and O 4- to 6-membered heterocyclic ring -CH ₂ -, wherein the maximum number of O heteroatoms is 1, optionally substituted by alkyl, optionally 1 to 2 independently selected from -OH, alkylamine 3- to 6-membered cycloalkyl substituted with substituents of -OH and dialkylamino; 4-membered cycloalkyl-CH optionally substituted with 1 or 2 substituents independently selected from -OH and alkyl ₂ -, and a 5-membered heteroaryl-CH ₂ - containing 2 N heteroatoms; and pharmaceutically acceptable salts. The compound according to any one of claims 1 to 6, wherein A ² is -O- or -NH-. The compound according to any one of claims 1 to 7, wherein A ² is -O-. The compound as any one of claims 1 to 3, wherein R is ^H , halo, alkyl, haloalkyl, haloalkoxy, cyano, alkoxy, cycloalkyl or alkylsulfonyl ; R ⁹ is H, alkyl, halo or cyano; or R ¹ and R ⁹ form a 5-membered heterocyclic ring containing a single O heteroatom. A compound as claimed in any one of claims 1 to 4, wherein R ¹ is halo, alkyl, haloalkyl or cyano; R ⁹ is H; or R ¹ and R ⁹ form a 5 member comprising a single O heteroatom heterocycle. The compound according to any one of claims 1 to 5, wherein R ¹ is halo or cyano and R ⁹ is H. The compound according to any one of claims 1 to 6, wherein R ² is alkyl or alkoxyalkyl and R ³ is H. The compound according to any one of claims 1 to 7, wherein R ⁸ is H. The compound as any one of claims 1 to 8, wherein ^R is selected from H, alkyl, acetyl, alkylamine, dialkylamine, hydroxyalkyl, hydroxyalkylalkyl, cyanide group, alkoxy group and NR'R'', wherein R' and R'' form a 4- to 5-membered N-containing heterocyclic ring optionally substituted by -OH, or a 5-membered internal acid with the N atom to which they are attached amine ring. The compound according to any one of claims 1 to 9, wherein R ¹⁰ is selected from H, cyano and alkoxy. The compound according to any one of claims 1 to 10, wherein R ¹⁰ is H. The compound according to any one of claims 1 to 11, wherein R ^X is H, alkoxyalkyl or hydroxyalkyl. The compound according to any one of claims 1 to 12, wherein R ^X is H. A compound as claimed in any one of claims 1 to 13, wherein W is selected from 4- to 10-membered heterocycles containing at most 3 heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1 , as the case may be, through 1 or 2 selected from side oxygen, -OH, halo, alkyl, alkoxyalkyl, alkylamino, dialkylaminoalkyl, hydroxyalkyl, haloalkyl , 4-membered cycloalkyl, 4-membered heterocycle containing 1 O heteroatom, 4-membered cycloalkyl substituted by -OH and substituents of 4-membered cycloalkyl-CH ₂ - substituted by -OH, including 4- to 6-membered heterocyclic ring -CH ₂ - with up to 2 heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1, optionally substituted by alkyl, optionally by -OH, alkane 3- to 6-membered cycloalkyl substituted by amino or dialkylamino, optionally 4-membered cycloalkyl-CH ₂ substituted by 1 or 2 substituents independently selected from -OH and alkyl -, and a 5-membered heteroaryl -CH ₂ - containing 2 N heteroatoms. A compound as claimed in any one of claims 1 to 14, wherein W is selected from 6 to 9 membered heterocycles containing at most 3 heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1 , optionally substituted with 1 or 2 substituents selected from pendant oxy, -OH, halo, alkyl and hydroxyalkyl, 6-membered heterocycle -CH ₂ - containing a single N heteroatom, via alkyl substituted, and 5-membered cycloalkyls substituted with dialkylamino groups. A compound as claimed in any one of claims 1 to 15, wherein W is a 6-membered heterocyclic ring containing a single N heteroatom, which is optionally substituted by an alkyl group or a pendant oxy group, or both an alkyl group and -OH. A compound as claimed in item 1, wherein A ¹ is -N- or -CR ¹⁰ -; A ² is -O- or -NH-; R ¹ is H, halo, alkyl, haloalkyl, haloalkoxy , cyano, alkoxy, cycloalkyl or alkylsulfonyl; R ⁹ is H, alkyl, halo or cyano; or R ¹ and R ⁹ form a 5-membered heterocyclic ring containing a single O heteroatom; R ^is H, halo, alkyl, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxyalkyl or hydroxyalkyl and ^R is H, halo or alkyl, wherein R At least one of ² and ^R3 is not H; ^R8 is H or halo; ^R10 is selected from H, alkyl, acetylalkylamine, dialkylamine, hydroxyalkyl, hydroxyl Alkylalkyl, cyano, alkoxy and NR'R'', where R' and R'' form, with the N atom to which they are attached, a 4- to 5-membered N-containing heterocyclic ring optionally substituted with -OH , or a 5-membered lactamide ring; n can be 0 or 1; R ^X is H, alkoxyalkyl or hydroxyalkyl; W is selected from the group consisting of at most 3 heteroatoms independently selected from N and O 4- to 10-membered heterocyclic rings, in which the maximum number of O heteroatoms is 1, optionally 1 or 2 selected from pendant oxy, -OH, halo, alkyl, alkoxyalkyl, alkylamine Dialkylaminoalkyl, hydroxyalkyl, haloalkyl, 4-membered cycloalkyl, 4-membered heterocycle containing a single O heteroatom, 4-membered cycloalkyl substituted with -OH, and 4-membered cycloalkyl substituted with -OH Substituents of 4-membered cycloalkyl-CH ₂ - , 4- to 6-membered heterocycles -CH ₂ - containing up to 2 heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1, optionally substituted with alkyl, optionally substituted with -OH, alkylamino or dialkylamino, 3- to 6-membered cycloalkyl, optionally with 1 or 2 independently selected from -OH and 4-membered cycloalkyl-CH ₂ -substituted by substituents of alkyl, and 5-membered heteroaryl-CH ₂ -containing 2 N heteroatoms; and pharmaceutically acceptable salts. A compound as in claim 1, wherein A ¹ is -N- or -CR ¹⁰ -; A ² is -O-; R ¹ is halo, alkyl, haloalkyl or cyano; R ⁹ is H; or R ¹ and ^R9 form a 5-membered heterocyclic ring containing a single O heteroatom; ^R2 is alkyl or alkoxyalkyl and ^R3 is H; ^R8 is H; ^R10 is selected from H, cyano and alkoxy n can be 0 or 1; R ^X is H; W is selected from 6 to 9 membered heterocyclic rings containing up to 3 heteroatoms independently selected from N and O, wherein the maximum number of O heteroatoms is 1 , optionally substituted with 1 or 2 substituents selected from pendant oxy, -OH, halo, alkyl and hydroxyalkyl, 6-membered heterocycle -CH ₂ - containing a single N heteroatom, via alkyl substituted, and 5-membered cycloalkyl substituted by dialkylamino; and pharmaceutically acceptable salts. Such as the compound of claim 1, wherein A ¹ is -N- or -CR ¹⁰ -; A ² is -O-; R ¹ is halo or cyano; R ⁹ is H; R ² is alkyl or alkoxy Alkyl and ^R3 is H; ^R8 is H; ^R10 is H; n can be 0 or 1; ^RX is H; Substituted by side oxygen, or both alkyl and -OH; and pharmaceutically acceptable salts. Such as the compound of claim 1, which is selected from (racemic)-2-[2-[(1-ethyl-3-piperidinyl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5 -(trifluoromethyl)phenol; (racemic)-2-[2-[3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3 - methyl-5-(trifluoromethyl)phenol; 2-[2-[(3R or 3S)-3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3 - methyl-5-(trifluoromethyl)phenol; 2-[2-[(3S or 3R)-3-[(dimethylamino)methyl]morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3 - methyl-5-(trifluoromethyl)phenol; (racemic)-1-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidine -3-ol; (3R or 3S)-1-[5-[2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidine -3-ol; (3S or 3R)-1-[5-[2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]piperidine -3-ol; 3-Methyl-2-(2-morpholinyloxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; (racemic)-[2-[2-(Hydroxymethyl)morpholin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(tri Fluoromethyl)phenol; 3-Methyl-2-(2-piperazin-1-yloxazolo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-[2-[[3-(methylamino)cyclohexyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl )phenol; 3-methyl-2-(2-piperazin-1-yl-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoromethyl)phenol; (racemic)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)oxazolo[4,5-b]pyridin-2-yl)piperidine -2-one; (racemic)-3-methyl-2-[2-[3-(methylamino)-1-piperidinyl]oxazolo[4,5-b]pyridin-5-yl]-5 -(trifluoromethyl)phenol; (racemic)-3-methyl-2-[2-(tetrahydropyran-3-ylamino)oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoro methyl) phenol; 1-[5-[2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]tetrahydroazia-3-ol ; 2-[2-[(3-Hydroxycyclohexyl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-( Trifluoromethyl)phenol; 3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-( Trifluoromethyl)phenol; (racemic)-3-methyl-2-(2-(1-methylpiperidin-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)-5-( Trifluoromethyl)phenol; (racemic)-3-methyl-2-(2-(pyrrolidin-2-yl)-1H-imidazo[4,5-b]pyridin-5-yl)-5-(trifluoro-methyl base) phenol; (racemic)-2-[2-[(1-ethyl-3-piperidinyl)amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl -5-(trifluoromethyl)phenol; 2-[2-[[(3R or 3S)-1-ethyl-3-piperidinyl]amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl -5-(trifluoromethyl)phenol; 2-[2-[[(3S or 3R)-1-ethyl-3-piperidinyl]amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl -5-(trifluoromethyl)phenol; and its pharmaceutically acceptable salts. Such as the compound of claim 1, which is selected from 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl -phenol; 5-Chloro-3-methyl-2-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1- base) oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[(3aS,7aR or 3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]zozolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 2-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]zozolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy- Benzonitrile; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methyl Oxymethyl) phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methyl Oxymethyl) phenol; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl - benzonitrile; 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] Benzonitrile; 4-[2-[(3aS,7aR or 3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; 4-[2-(1,2,3,5,6,7,8,8a-Swainson-8-ylamino)oxazolo[4,5-b]pyridin-5-yl]- 3-Hydroxy-5-methyl-benzonitrile; 3-(Difluoromethyl)-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] -5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-5- (Trifluoromethyl)phenol; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-5- (Trifluoromethyl)phenol; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-5- (Trifluoromethyl)phenol; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methoxy-5- (Trifluoromethyl)phenol; 2-[2-[(1-Ethyl-3-piperidinyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoroform base) phenol; 2-[2-[(1-Ethyl-3-piperidinyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoroform base) phenol; 3-Methyl-2-[7-methyl-2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-5-(trifluoromethyl)phenol; 3-Methyl-2-[7-methyl-2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-5-(trifluoromethyl)phenol; 5-Methoxy-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridine-5- Base] phenol; 5-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]-6-methyl-oxazolo[4,5-b]pyridin-5-yl]-2, 3-Dihydrobenzofuran-4-ol; 5-Cyclopropyl-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridine-5- Base] phenol; and its pharmaceutically acceptable salts. Such as the compound of claim 1, which is selected from 2-[2-[(3aS,7aR)-6-Methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]㗁Azolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol or 2-[2-[(3aR,7aS)-6-methyl-3, 3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl Base-5-(trifluoromethyl)phenol; 2-[2-[(3aR,7aS)-6-Methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]㗁Azolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol or 2-[2-[(3aS,7aR)-6-methyl-3, 3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl Base-5-(trifluoromethyl)phenol; (racemic)-3-methyl-2-[2-(tetrahydrofuran-3-ylamino)oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl) phenol; 5-Chloro-3-methyl-2-[2-[[rac-(8S,8aR)-1,2,3,5,6,7,8,8a-swainson-8-yl ]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[[(8S,8aR)-1,2,3,5,6,7,8,8a-swainson-8-yl]amino]oxazolo[4,5-b ]pyridin-5-yl]-5-chloro-3-methyl-phenol or 2-[2-[[(8R,8aS)-1,2,3,5,6,7,8,8a-octahydro Indolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 2-[2-[[(8R,8aS)-1,2,3,5,6,7,8,8a-swainson-8-yl]amino]oxazolo[4,5-b ]pyridin-5-yl]-5-chloro-3-methyl-phenol or 2-[2-[[(8S,8aR)-1,2,3,5,6,7,8,8a-octahydro Indolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 5-chloro-3-methyl-2-[2-(6-methyl-3,4a,5,7,8,8a-hexahydro-2H-pyrido[4,3-b][1,4 ](azin-4-yl)(oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-(2-Azabicyclo[2.1.1]hex-1-ylmethylamino)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5- (Trifluoromethyl)phenol; Dihydrochloride; 5-Chloro-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] phenol; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-fluoro-3-methyl -phenol; 5-Chloro-3-methyl-2-[2-[[(3R)-1-propyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] phenol; 5-Chloro-2-[2-[[(3R)-1-cyclobutyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl Base-phenol; 5-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3 - dihydrobenzofuran-4-ol; (3S,5R)-5-[[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1 -Methyl-piperidin-3-ol; 5-Fluoro-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] phenol; (3S,5R)-1-Ethyl-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridine- 2-yl]amino]piperidin-3-ol; 2-[2-[[(3R)-1-(2-Hydroxyethyl)-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl Base-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-fluoro-5-(tri Fluoromethyl)phenol; 5-Chloro-2-[2-[[(3R,5S)-1-ethyl-5-fluoro-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-3-methyl-phenol; 2-[2-[[(1R,2R)-2-(Dimethylamino)cyclopropyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl -5-(trifluoromethyl)phenol; 3-Hydroxy-4-[2-[[(3R,5S)-5-hydroxy-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-5-methyl-benzonitrile; cis-2-[2-[(3-hydroxy-3-methyl-cyclobutyl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl- 5-(trifluoromethyl)phenol; trans-2-[2-[(3-Hydroxy-3-methyl-cyclobutyl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl- 5-(trifluoromethyl)phenol; 5-Chloro-2-[2-[(1-ethyltetrahydroazine-3-yl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl -phenol; 1-[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)-2-[[racemic-(3R)-1-methyl-3-piperidinyl]amino]㗁Azolo[4,5-b]pyridin-7-yl]pyrrolidin-2-one; 2-[2-[[(3R)-1-(3-Hydroxycyclobutyl)-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Methyl-5-(trifluoromethyl)phenol; 2-[2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)oxazolo[4,5-b]pyridin-5-yl ]-3-methyl-5-(trifluoromethyl)phenol; 5-Chloro-3-methyl-2-[2-[[(3R)-1-(oxetane-3-yl)-3-piperidinyl]amino]oxazolo[4,5 -b]pyridin-5-yl]phenol; 3-Methyl-2-[2-[rel-(4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4] Oxazin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid; 2-[2-[(4aS,7aS)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl] Zazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[2-[(4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-4-yl] Zazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; N-(1,2,3,5,6,7,8,8a-swainson-6-yl)-5-chloro-oxazolo[4,5-b]pyridin-2-amine; 3-Methyl-2-[2-[[(2S)-1-methyltetrahydroazil-2-yl]methylamino]oxazolo[4,5-b]pyridin-5-yl] -5-(trifluoromethyl)phenol or 3-methyl-2-[2-[[(2R)-1-methyltetrahydroazine-2-yl]methylamino]oxazolo[4 ,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 3-Methyl-2-[2-[[(2R)-1-methyltetrahydroazia-2-yl]methylamino]oxazolo[4,5-b]pyridin-5-yl] -5-(trifluoromethyl)phenol or 3-methyl-2-[2-[[(2S)-1-methyltetrahydroazine-2-yl]methylamino]oxazolo[4 ,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 3-Methyl-2-[2-[(1-methyltetrahydroazine-2-yl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-5-( Trifluoromethyl)phenol; 5-Chloro-2-[2-(1H-imidazol-5-ylmethylamino)zozolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; (3RS,5R)-5-[[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1 -Ethyl-piperidin-3-ol; formic acid; 3,6-Dimethyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol ; (3R,5R)-5-[[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1 -Ethyl-piperidin-3-ol; formic acid; 4-[2-[[(3R,5R)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; 4-[2-[(3aS,7aR)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]㗁Azolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[(3aR,7aS)-6-ethyl-3,3a,4 ,5,7,7a-Hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxyl-5- Methyl-benzonitrile; 4-[2-[(3aR,7aS)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]㗁Azolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[(3aS,7aR)-6-ethyl-3,3a,4 ,5,7,7a-Hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxyl-5- Methyl-benzonitrile; 5-[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; (5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or ( 5R)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; (5R)-5-[5-(4-chloro-2-hydroxyl-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or ( 5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; 5-Chloro-2-[2-[[(3R)-1-(3,3-difluoropropyl)-3-piperidinyl]amino]oxazolo[4,5-b]pyridine-5 -yl]-3-methyl-phenol; 5-Chloro-3-methyl-2-[2-[[(3R)-1-[(3-hydroxycyclobutyl)methyl]-3-piperidinyl]amino]oxazolo[4, 5-b]pyridin-5-yl]phenol; 5-Chloro-2-[2-(1H-imidazol-2-ylmethylamino)zozolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 2-[2-[3-(Hydroxymethyl)-1-piperidinyl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl) phenol; 2-[2-[4-(Hydroxymethyl)-1-piperidinyl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl) phenol; 2-[2-(1-Ethyl-1,7-diazaspiro[3.5]non-7-yl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl- 5-(trifluoromethyl)phenol; 3-Hydroxy-5-methyl-4-[2-[racemic trans-6-ethyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][ 1,4]-oxazin-4-yl]oxazolo[4,5-b]pyridin-5-yl]benzonitrile; 3-Hydroxy-5-methyl-4-[2-(7-methyl-2,3,4,4a,5,6,8,8a-octahydro-1,7-phenidin-1-yl) Zazolo[4,5-b]pyridin-5-yl]benzonitrile; 2-Hydroxy-4-methyl-3-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] Benzonitrile; 2,2,2-trifluoroacetic acid; 5-Chloro-3-methyl-2-[2-[(1-methyl-3-piperidinyl)methyl]oxazolo[4,5-b]pyridin-5-yl]phenol; 4-[(3R)-3-[[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]- 1-piperidinyl]butyric acid methyl ester; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] -5-methyl-benzonitrile; 3-[(3R)-3-[[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]- Methyl 1-piperidinyl]propionate; 5-Chloro-2-[2-[[6-(hydroxymethyl)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]- 3-methyl-phenol; 2,2,2-trifluoroacetic acid; 5-Chloro-2-[2-[(4-isopropylmorpholin-2-yl)methyl]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; formic acid; 3-Methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-methyl Sulfonyl-phenol; 2,2,2-trifluoroacetic acid; 5-Chloro-2-[2-[2-methoxyethyl-[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridine-5 -yl]-3-methyl-phenol; formic acid; 2-[2-[[(3R)-1-Ethylnitro-3-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-( Trifluoromethyl)phenol; 5-Chloro-2-[2-[(3-hydroxycyclobutyl)methylamino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] -3-methyl-phenol; 5-Chloro-3-(hydroxymethyl)-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridine-5 -base] phenol; 5-Chloro-2-[2-[[(3R)-1-(3-hydroxypropyl)-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] -3-methyl-phenol; 5-Chloro-3-methyl-2-[2-[[rac-(3R)-1-(2-hydroxypropyl)-3-piperidinyl]amino]oxazolo[4,5 -b]pyridin-5-yl]phenol; 5-Chloro-2-[2-[2-hydroxyethyl-[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-3-methyl-phenol; 5-Chloro-2-[2-[[(3S,4R)-1-ethyl-4-fluoro-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-3-methyl-phenol; 5-Chloro-2-[2-[[(3R,4S)-1-ethyl-4-fluoro-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-3-methyl-phenol; (3S,5R)-5-[[5-[4-Chloro-2-hydroxy-6-(methoxymethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amine Base] -1-methyl-piperidin-3-ol; 1-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]-5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]㗁Azolo[4,5-b]pyridin-7-yl]tetrahydroacrin-3-ol; 1-[5-[2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-2-[[(3R)-1-methyl-3-piperidinyl]amino]㗁Azolo[4,5-b]pyridin-7-yl]ethanone; 2,2,2-trifluoroacetic acid; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]-7-(methylamino)oxazolo[4,5-b]pyridin-5-yl] -3-methyl-5-(trifluoromethyl)phenol; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3 - methyl-5-(trifluoromethyl)phenol; 2-[7-(1-Hydroxy-1-methyl-ethyl)-2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b ]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid; 2-[7-(1-Hydroxyethyl)-2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-3-methyl-5-(trifluoromethyl)phenol; 3-Chloro-4-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-hydroxy- Benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(1R,2R)-2-(Dimethylamino)cyclopentyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy- 5-methyl-benzonitrile; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methyl Base-benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxyl-5-(methyl oxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3 -Hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 5-Chloro-2-[2-[[(1R,2R)-2-(dimethylamino)cyclopentyl]amino]oxazolo[4,5-b]pyridin-5-yl]- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methanol Base-phenol; 2,2,2-trifluoroacetic acid; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(tri fluoromethoxy)phenol; 2,2,2-trifluoroacetic acid; 3-Hydroxy-5-methyl-4-[2-[[(2S)-2-hydroxy-1,2,3,5,6,7,8,8a-swainson-8-yl]amine Base] oxazolo[4,5-b]pyridin-5-yl]benzonitrile; 2,2,2-trifluoroacetic acid; 2-[7-(Dimethylamino)-2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-3-methyl-5-(trifluoromethyl)phenol; 2-[[(3R)-1-ethyl-3-piperidinyl]amino]-5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[ 4,5-b]pyridine-7-carbonitrile; 5-Chloro-2-[2-[[(3R)-1-[[racemic trans-2-hydroxycyclobutyl]methyl]-3-piperidinyl]amino]oxazolo[4 ,5-b]pyridin-5-yl]-3-methyl-phenol or 5-chloro-2-[2-[[(3R)-1-[[racemic cis-2-hydroxycyclobutyl ]methyl]-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-[[racemic trans-2-hydroxycyclobutyl]methyl]-3-piperidinyl]amino]oxazolo[4 ,5-b]pyridin-5-yl]-3-methyl-phenol or 5-chloro-2-[2-[[(3R)-1-[[racemic cis-2-hydroxycyclobutyl ]methyl]-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-benzonitrile; 3-methyl-2-[2-[(2-methyl-2-azabicyclo[2.2.2]oct-4-yl)amino]oxazolo[4,5-b]pyridine-5- Base] -5- (trifluoromethyl) phenol; 5-(Difluoromethyl)-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridine -5-yl]phenol; 5-(Difluoromethyl)-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] -3-methyl-phenol; 2,2,2-trifluoroacetic acid; 5-(Difluoromethyl)-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] -3-methyl-phenol; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3,5-dimethyl- phenol; 3-[[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1-ethyl-piperidine -4-ol; 2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 5-fluoro-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(tri fluoromethyl)phenol; 2,2,2-trifluoroacetic acid; 5-Chloro-2-[6-chloro-2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol ; 3,5-Dimethyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol ; 2,2,2-trifluoroacetic acid; 3-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-fluoro- Phenol; 2,2,2-Trifluoroacetic acid; 5-(Difluoromethoxy)-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-3-methyl-phenol; 2,2,2-trifluoroacetic acid; 2-[2-[(1-Ethylpyrrolidin-3-yl)amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl )phenol; 3,5-dichloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 2,2,2-Trifluoroacetic acid; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]-6-fluoro-1H-imidazo[4,5-b]pyridin-5-yl]-5- (Trifluoromethyl)phenol; (3S,5R)-5-[[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1 - Ethyl-piperidin-3-ol; 3-Methyl-2-[2-[4-(methylamino)tetrahydropyran-4-yl]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoro Methyl)phenol; 2,2,2-trifluoroacetic acid; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]-3H-imidazo[4,5-b]pyridin-5-yl]-3- Methyl-phenol; 2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-( trifluoromethoxy)phenol; 2,2,2-trifluoroacetic acid; 2-[2-(1-Ethyl-3-piperidinyl)oxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(trifluoromethyl)phenol; 4-[2-[[(8R,8aR)-1,2,3,5,6,7,8,8a-swainson-8-yl]amino]oxazolo[4,5-b ]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[[(8S,8aS)-1,2,3,5,6,7,8,8a-octa Hydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(8S,8aS)-1,2,3,5,6,7,8,8a-swainson-8-yl]amino]oxazolo[4,5-b ]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[[(8R,8aR)-1,2,3,5,6,7,8,8a-octa Hydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; and its pharmaceutically acceptable salts. Such as the compound of claim 1, which is selected from (racemic)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)oxazolo[4,5-b]pyridin-2-yl)piperidine -2-one; 2-[2-[[(3R or 3S)-1-ethyl-3-piperidinyl]amino]-1H-imidazo[4,5-b]pyridin-5-yl]-3-methyl -5-(trifluoromethyl)phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl -phenol; 5-Chloro-3-methyl-2-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1- base) oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]zozolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy- Benzonitrile; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methyl Oxymethyl) phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methyl Oxymethyl) phenol; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl - benzonitrile; 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] Benzonitrile; 4-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; 4-[2-(1,2,3,5,6,7,8,8a-Swainson-8-ylamino)oxazolo[4,5-b]pyridin-5-yl]- 3-Hydroxy-5-methyl-benzonitrile; 2-[2-[(1-Ethyl-3-piperidinyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoroform base) phenol; 2-[2-[(1-Ethyl-3-piperidinyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoroform base) phenol; 3-Methyl-2-[7-methyl-2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-5-(trifluoromethyl)phenol; 3-Methyl-2-[7-methyl-2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-5-(trifluoromethyl)phenol; 5-Methoxy-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridine-5- Base] phenol; 5-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]-6-methyl-oxazolo[4,5-b]pyridin-5-yl]-2, 3-Dihydrobenzofuran-4-ol; and its pharmaceutically acceptable salts. Such as the compound of claim 1, which is selected from (racemic)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)oxazolo[4,5-b]pyridin-2-yl)piperidine -2-one; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl -phenol; 5-Chloro-3-methyl-2-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1- base) oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]zozolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-4-fluoro- 3-methyl-phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy- Benzonitrile; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methyl Oxymethyl) phenol; 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-(methyl Oxymethyl) phenol; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl - benzonitrile; 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] Benzonitrile; 4-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; 4-[2-(1,2,3,5,6,7,8,8a-Octahydroindolizin-8-ylamino)oxazolo[4,5-b]pyridine-5- Base]-3-hydroxy-5-methyl-benzonitrile; 2-[2-[(1-Ethyl-3-piperidinyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoroform base) phenol; 2-[2-[(1-Ethyl-3-piperidinyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoroform base) phenol; 5-Methoxy-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridine-5- Base] phenol; and its pharmaceutically acceptable salts. Such as the compound of claim 1, which is selected from 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl -phenol; 5-Chloro-3-methyl-2-[2-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1- base) oxazolo[4,5-b]pyridin-5-yl]phenol; 2-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]zozolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl - benzonitrile; 3-Hydroxy-5-methyl-4-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] Benzonitrile; 4-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; 2-[2-[(1-Ethyl-3-piperidinyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoroform base) phenol; 2-[2-[(1-Ethyl-3-piperidinyl)amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(trifluoroform base) phenol; and its pharmaceutically acceptable salts. Such as the compound of claim 1, which is selected from 5-Chloro-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl -phenol; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl - benzonitrile; 4-[2-[(3aR,7aS or 3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1 -yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; and its pharmaceutically acceptable salts. Such as the compound of claim 1, which is selected from 2-[2-[[(8R,8aS)-1,2,3,5,6,7,8,8a-swainson-8-yl]amino]oxazolo[4,5-b ]pyridin-5-yl]-5-chloro-3-methyl-phenol or 2-[2-[[(8S,8aR)-1,2,3,5,6,7,8,8a-octahydro Indolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-chloro-3-methyl-phenol; 5-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3 - dihydrobenzofuran-4-ol; (3S,5R)-5-[[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1 -Methyl-piperidin-3-ol; 3-Hydroxy-4-[2-[[(3R,5S)-5-hydroxy-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-5-methyl-benzonitrile; 3-Methyl-2-[2-[rel-(4aR,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4] Oxazin-4-yl]oxazolo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol; 2,2,2-trifluoroacetic acid; (3R,5R)-5-[[5-(4-Chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-1 -Ethyl-piperidin-3-ol; formic acid; 4-[2-[[(3R,5R)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; 4-[2-[(3aS,7aR)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]㗁Azolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[(3aR,7aS)-6-ethyl-3,3a,4 ,5,7,7a-Hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxyl-5- Methyl-benzonitrile; (5R)-5-[5-(4-chloro-2-hydroxyl-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or ( 5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; 5-Chloro-3-methyl-2-[2-[(1-methyl-3-piperidinyl)methyl]oxazolo[4,5-b]pyridin-5-yl]phenol; 3-Hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] -5-methyl-benzonitrile; 5-Chloro-2-[2-[[(3S,4R)-1-ethyl-4-fluoro-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl ]-3-methyl-phenol; (3S,5R)-5-[[5-[4-Chloro-2-hydroxy-6-(methoxymethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amine Base] -1-methyl-piperidin-3-ol; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3 - methyl-5-(trifluoromethyl)phenol; 4-[2-[[(1R,2R)-2-(Dimethylamino)cyclopentyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy- 5-methyl-benzonitrile; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methyl Base-benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxyl-5-(methyl oxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3 -Hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 2-[[(3R)-1-ethyl-3-piperidinyl]amino]-5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[ 4,5-b]pyridine-7-carbonitrile; 5-(Difluoromethyl)-3-methyl-2-[2-[[(3R)-1-methyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridine -5-yl]phenol; 5-(Difluoromethyl)-2-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl] -3-methyl-phenol; 2-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3,5-dimethyl- phenol; 4-[2-[[(8S,8aS)-1,2,3,5,6,7,8,8a-swainson-8-yl]amino]oxazolo[4,5-b ]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile or 4-[2-[[(8R,8aR)-1,2,3,5,6,7,8,8a-octa Hydroindolizin-8-yl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; and its pharmaceutically acceptable salts. Such as the compound of claim 1, which is selected from 4-[2-[[(3R,5R)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; (5R)-5-[5-(4-chloro-2-hydroxyl-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or ( 5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methyl Base-benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxyl-5-(methyl oxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid; and its pharmaceutically acceptable salts. Such as the compound of claim 1, which is selected from 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl - benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3- Hydroxy-5-methyl-benzonitrile; formate; (5R)-5-[5-(4-chloro-2-hydroxyl-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one or ( 5S)-5-[5-(4-chloro-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]piperidin-2-one; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methyl Base-benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-Ethyl-3-piperidinyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxyl-5-(methyl oxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidinyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3 -Hydroxy-5-methyl-benzonitrile; 2,2,2-trifluoroacetic acid; and its pharmaceutically acceptable salts. A method for preparing a compound as claimed in any one of claims 1 to 29, comprising reacting a compound of formula X to a compound of formula Ic according to the following scheme, wherein R ¹ , R ² , R ³ , R ⁸ , R ⁹ , R ^X , n and W are as described above, A ¹ is N and A ² is O. The compound according to any one of claims 1 to 29, which is produced according to the method of claim 30. A compound according to any one of claims 1 to 29 for use as a therapeutically active substance. A compound according to any one of claims 1 to 29 for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition. A pharmaceutical composition comprising the compound according to any one of claims 1 to 29 and a therapeutically inert carrier. A use of a compound according to any one of claims 1 to 29 for the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition. A compound according to any one of claims 1 to 29 for use in the treatment or prevention of a disease, disorder or condition selected from asthma or COPD. A use of a compound according to any one of claims 1 to 29 for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD. A use of a compound according to any one of claims 1 to 29 for the preparation of a medicament for treating or preventing a disease, disorder or condition selected from asthma or COPD. A method of inhibiting NLRP3, the method comprising administering an effective amount of the compound according to any one of claims 1 to 29 to inhibit NLRP3. A method of treating or preventing a disease, disorder or condition comprising administering an effective amount of a compound according to any one of claims 1 to 29, wherein the disease, disorder or condition is selected from asthma or COPD. The present invention as described above.